Compositions for reduction of side effects

ABSTRACT

The present invention provides drug therapy formulations. In some embodiments, the present invention provides combinations of pharmaceutical agents (e.g., stimulant and non-stimulant), pharmaceutical formulations (e.g., nanoparticulate, non-nanoparticulate, etc.), and release profiles (e.g., immediate release, delayed release, sustained release, etc.) to provide therapeutic benefit with reduced side effects.

This application claims priority to provisional patent application Ser.No. 61/550,119, filed Oct. 21, 2011 and provisional patent applicationSer. No. 61/609,590 filed Mar. 12, 2012, and is a Continuation-in-partof U.S. application Ser. No. 13/093,662, filed Apr. 25, 2011, whichclaims priority to provisional patent application Ser. No. 61/327,486,filed Apr. 23, 2010 and provisional patent application Ser. No.61/369,338 filed Jul. 30, 2010, all of which are herein incorporated byreference in their entireties.

FIELD OF THE INVENTION

The present invention provides drug therapy formulations. In someembodiments, the present invention provides combinations ofpharmaceutical agents (e.g., stimulant and non-stimulant),pharmaceutical formulations (e.g., nanoparticulate, non-nanoparticulate,etc.), and release profiles (e.g., immediate release, delayed release,sustained release, etc.) to provide therapeutic benefit with reducedside effects.

BACKGROUND

Attention deficit hyperactivity disorder (ADHD) is one of the mostcommon childhood mental disorders. Children with ADHD have impairedfunctioning in multiple settings, including home and school. The adverseeffects can last into adolescence and adulthood. Since schools do notencourage medication administration during school hours, most childrenare given once daily stimulants such as Vyvanse & Adderall XR(amphetamine based), Focalin XR, or Concerta (methylphenidate based).However the activity of the once daily stimulants lasts well into theevening hours leading to significant side effects such as appetitesuppression and weight loss as well as insomnia and gastro intestinalpain. These are described in detail on the FDA approved labels for thesedrugs. Non-stimulants such as Intuniv (guanfacine) and Strattera(atomoxetine) at higher doses lead to significant side effects such ascardiovascular effects such as hypertension as well as somnolence.

Drug side effects, including difficulty sleeping, loss of appetite, andabdominal pain, are a significant medical issue. Insomnia, difficultyfalling asleep, or difficulty remaining asleep can result in problemsleepiness, which impairs the health, quality of life and safety ofthose affected. Appetite disorders, such as loss of appetite, can causereduced energy, health, quality of life, and can cause additionaldownstream nutritional deficiencies. Abdominal pain can greatly reducethe quality of life for a patient, and greatly reduce compliance with atherapy regimen. Another ADHD drug-related side effect includesexacerbation of tics, particularly for children with underlyingdisorders that may cause tics. Also, children and adolescents using highdoses of stimulant drugs may have slowed or stunted growth. Drug sideeffects often become more pronounced as drug dosages are increased toachieve longer lasting benefits.

Attention deficit hyperactive disorder (ADHD) is commonly treated withstimulants (e.g. norepinephrine reuptake inhibitors (e.g. amphetamines,methylphenidate, etc.)). In order to provide sufficient therapeuticbenefit throughout the day, a large dose morning dose is commonlyadministered. Such large doses of stimulants are frequently associatedwith significant side effects, including insomnia, abdominal pain, andloss of appetite. Children administered large doses of stimulants canalso experience slowed or reduced growth resulting in diminished height.Children, who commonly suffer from ADHD, are particularly susceptible todisruption of sleep and/or eating habits and the additional downstreamconsequences thereof.

SUMMARY OF THE INVENTION

Administration of conventional therapeutically effective doses ofstimulants for the treatment of ADHD, ADHD symptoms, or similarconditions and disorders can result in numerous adverse side effects forthe patient. These side effects include: appetite suppression (e.g.,caused by long acting once-daily stimulants or twice dailyadministrations of stimulant) which can lead to weight loss, insomnia,stunted growth in adolescent and pediatric populations (e.g., caused bylong-term use of high dose stimulants), and gastro-intestinal pain(e.g., caused by the enteric release of stimulants (e.g., high dosestimulants)) in the intestine. Likewise, conventional therapeuticallyeffective dose of non-stimulants for treatment of ADHD symptoms canresult in cardiovascular issues. Other issues with current stimulantADHD treatments include slow absorption and onset of action. The presentinvention provides compositions, formulations, and methods foreffectively treating ADHD symptoms while reducing adverse side effectsvia a variety of alternative or complementary approaches, for example:the daily stimulant dose is reduced by delivering stimulant between 0and 7 hours post-administration and having very low levels of thestimulant in the blood by 12 hours post-administration, deliveringstimulant between 0 and 7 hours post-administration along withnon-stimulant from 2-14 hours post-administration to offsetpharmacologically the stimulant insomnia, not releasing stimulant in theintestine, releasing only a low dose of stimulant in the intestine alongwith peppermint oil, and providing only a low dose of non-stimulant. Thepresent invention also addresses the above issues throughnanoparticulate formulation of stimulant resulting in rapid onset ofaction and/or earlier clearance of stimulant post-administration. Theabove embodiments are exemplary; other embodiments are described in theSummary below and in the Detailed Description.

In some embodiments, the present invention provides pharmaceuticalcompositions comprising: (a) an amount of norepinephrine reuptakeinhibitor stimulant that is subtherapeutic for once dailyadministration; and (b) an amount of alpha adrenergic agonist nonstimulant that is subtherapeutic for once daily administration; whereinthe pharmaceutical composition is formulated for sequential release ofthe norepinephrine reuptake inhibitor stimulant and the alpha adrenergicagonist non stimulant, and wherein sequential release of thenorepinephrine reuptake inhibitor stimulant and the alpha adrenergicagonist non stimulant provides therapeutic effectiveness for once dailyadministration. In some embodiments, the norepinephrine reuptakeinhibitor stimulant is formulated to begin release upon administrationto a subject. In some embodiments, the norepinephrine reuptake inhibitorstimulant is formulated for release between 0 and 2 hourspost-administration. In some embodiments, the norepinephrine reuptakeinhibitor stimulant is nanoparticulate formulated. In some embodiments,the alpha adrenergic agonist non stimulant is coated for entericrelease. In some embodiments, the alpha adrenergic agonist non stimulantis formulated for release between 2 and 9 hours post-administration. Insome embodiments, the amount of norepinephrine reuptake inhibitorstimulant is at least 20% less (e.g., >20% less, >30% less, >40%less, >50% less) than a therapeutic formulation. In some embodiments,the amount of alpha adrenergic agonist non stimulant is at least 20%less (e.g., >20% less, >30% less, >40% less, >50% less) than atherapeutic formulation. In some embodiments, the norepinephrinereuptake inhibitor stimulant is selected from amphetamines,lisdexamphetamines, methylphenidates, dexmethylphenidates, anddexamphetamines. In some embodiments, the alpha adrenergic agonist nonstimulant is selected from Atomoxetine, Guanfacine, and Clonidine. Insome embodiments, the present invention provides methods of treatingADHD by administering one or the above pharmaceutical compositions of toa subject, wherein the pharmaceutical composition is administered onceper day to the subject.

In some embodiments, the present invention provides methods of treatingADHD symptoms while reducing adverse stimulant-related side effects byadministering a once-daily pharmaceutical composition containing anotherwise subtherapeutic dose of a stimulant pharmaceutical agent, thepharmaceutical composition comprising: (a) a nanoparticulate formulatedstimulant; (b) stimulant formulated for early or immediate release; (c)both stimulant pharmaceutical agent and non-stimulant pharmaceuticalagent; or (d) a combination of two or more of (a), (b), and (c). In someembodiments, the adverse stimulant-related side effects compriseappetite suppression. In some embodiments, the appetite suppressionmanifests as weight loss in a subject. In some embodiments, the adversestimulant-related side effects comprise insomnia. In some embodiments,the adverse stimulant-related side effects comprise stunted growth of asubject.

In some embodiments, present invention provides pharmaceuticalcompositions for treating ADHD symptoms with a once-daily stimulantpharmaceutical agent while reducing gastrointestinal adverse sideeffects comprising administering a pharmaceutical compositioncomprising: (a) an immediate- or early-release pharmaceuticalformulation comprising an amount of stimulant pharmaceutical agent thatis subtherapeutic for once daily administration; and (b) adelayed-release pharmaceutical formulation comprising: (i) anon-stimulant pharmaceutical agent, an amount of stimulantpharmaceutical agent that is subtherapeutic for once dailyadministration, and peppermint oil; (ii) a non-stimulant pharmaceuticalagent and peppermint oil; or (iii) a non-stimulant pharmaceutical agent.In some embodiments, the immediate- or early-release pharmaceuticalformulation provides release between 0 and 2 hours post-administration.In some embodiments, the immediate- or early-release pharmaceuticalformulation comprises nanoparticulate formulation. In some embodiments,the stimulant pharmaceutical agent formulated for immediate- orearly-release is selected from amphetamines, lisdexamphetamines,methylphenidates, dexmethylphenidates, and dexamphetamines. In someembodiments, the amount of stimulant pharmaceutical agent in theimmediate- or early-release pharmaceutical formulation is about 5-15 mg.In some embodiments, the delayed-release pharmaceutical formulationprovides release between 2 and 9 hours post-administration. In someembodiments, the delayed-release is provided by an enteric coatingcoated. In some embodiments, the non-stimulant pharmaceutical agentselected from Atomoxetine, Guanfacine, and Clonidine. In someembodiments, the delayed-release pharmaceutical formulation comprisesabout 1-4 mg of non-stimulant. In some embodiments, the delayed-releasepharmaceutical formulation comprises amount of stimulant pharmaceuticalagent that is subtherapeutic for once daily administration, wherein theamount is about 3-8 mg. In some embodiments, the stimulantpharmaceutical agent is selected from amphetamines, lisdexamphetamines,methylphenidates, dexmethylphenidates, and dexamphetamines. In someembodiments, the present invention provides methods of treating ADHD byadministering one or the above pharmaceutical compositions of to asubject, wherein the pharmaceutical composition is administered once perday to the subject.

In some embodiments, the present invention provides rapid onsetstimulant pharmaceutical formulations comprising nanoparticulateformulated stimulant and a pharmaceutically acceptable carrier. In someembodiments, the amount of stimulant pharmaceutical agent issubtherapeutic for once daily administration. In some embodiments, theamount of stimulant pharmaceutical agent is at least 20% less than atherapeutic formulation. In some embodiments, the stimulantpharmaceutical agent is formulated for release between 0 and 2 hourspost-administration. In some embodiments, the particles in thenanoparticulate formulation are less than 1000 microns in diameter. Insome embodiments, the nanoparticulate formulation has a meannanoparticle diameter of 100-500 nm. In some embodiments, presentinvention provides methods of treating ADHD by administering a rapidonset stimulant pharmaceutical composition to a subject.

In some embodiments, the present invention provides pharmaceuticalcompositions for extended duration of treatment of ADHD symptomscomprising: (a) an immediate- or early-release pharmaceuticalformulation comprising an amount of stimulant pharmaceutical agent thatis subtherapeutic for once daily administration; and (b) adelayed-release pharmaceutical formulation comprising a non-stimulantpharmaceutical agent. In some embodiments, the immediate- orearly-release pharmaceutical formulation provides release between 0 and2 hours post-administration. In some embodiments, the immediate- orearly-release pharmaceutical formulation comprises nanoparticulateformulation. In some embodiments, the stimulant pharmaceutical agentformulated for immediate- or early-release is selected fromamphetamines, lisdexamphetamines, methylphenidates, dexmethylphenidates,and dexamphetamines. In some embodiments, the amount of stimulantpharmaceutical agent in the immediate- or early-release pharmaceuticalformulation is about 5-15 mg. In some embodiments, the delayed-releasepharmaceutical formulation provides release between 2 and 9 hourspost-administration. In some embodiments, the delayed-release isprovided by an enteric coating coated. In some embodiments, thenon-stimulant pharmaceutical agent selected from Atomoxetine,Guanfacine, and Clonidine. In some embodiments, the delayed-releasepharmaceutical formulation comprises about 1-4 mg of non-stimulant. Insome embodiments, the delayed-release pharmaceutical formulation furthercomprises a second amount of stimulant pharmaceutical agent that issubtherapeutic for once daily administration. In some embodiments, thesecond amount of stimulant pharmaceutical agent is about 3-8 mg. In someembodiments, the second amount of stimulant pharmaceutical agent isselected from amphetamines, lisdexamphetamines, methylphenidates,dexmethylphenidates, and dexamphetamines. In some embodiments, In someembodiments, methods are provided for treating ADHD by administering oneor the aforementioned pharmaceutical compositions to a subject, whereinthe pharmaceutical composition is administered once per day to thesubject.

In some embodiments, the present invention provides methods forproducing an amphetamine nanoparticulate formulation comprising: (a)forming a mixture of amphetamine and one or more vehicles; (b) millingthe mixture; and (c) drying the mixture. In some embodiments, theamphetamine comprises l-amphetamine, d-amphetamine. In some embodiments,the particles in the amphetamine nanoparticulate formulation are lessthan 1000 microns in diameter. In some embodiments, the amphetaminenanoparticulate formulation has a mean nanoparticle diameter of 100-500nm.

In some embodiments, the present invention provides pharmaceuticalcompositions comprising a stimulant pharmaceutical agent and anon-stimulant pharmaceutical agent, wherein the upon administration to asubject, the pharmaceutical composition provides a plasma concentrationprofile comprising a stimulant maximum between 0 and 2 hourspost-administration and a non-stimulant maximum between 2 and 9 hourspost-administration. In some embodiments, all or a portion of thestimulant pharmaceutical agent is nanoparticulate formulated. In someembodiments, the stimulant pharmaceutical agent is selected fromamphetamines, lisdexamphetamines, methylphenidates, dexmethylphenidates,and dexamphetamines. In some embodiments, the stimulant maximum between0 and 2 hours post-administration is the effect of about 5-15 mg of thestimulant pharmaceutical agent. In some embodiments, the non-stimulantpharmaceutical agent is enterically coated. In some embodiments, thenon-stimulant pharmaceutical agent is selected from Atomoxetine,Guanfacine, and Clonidine. In some embodiments, the plasma concentrationprofile comprises a second stimulant maximum between 2 and 7 hourspost-administration. In some embodiments, the stimulant pharmaceuticalagent that gives rise to the second stimulant maximum is selected fromamphetamines, lisdexamphetamines, methylphenidates, dexmethylphenidates,and dexamphetamines. In some embodiments, the second stimulant maximumbetween 2 and 7 hours post-administration is the effect of about 3-8 mgof stimulant pharmaceutical agent. In some embodiments, the stimulantpharmaceutical agent that gives rise to the second stimulant maximum isenterically coated. In some embodiments, the present invention providesmethods of treating ADHD symptoms in a subject comprising administeringone of the above pharmaceutical compositions to the subject.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a stimulant pharmacologic agent (e.g., agent fortreatment of ADHD or other psychiatric conditions) and a non-stimulantpharmacologic agent for treatment of ADHD (e.g., agent for treatment ofADHD or other psychiatric conditions), wherein the stimulantpharmacologic agent and the non-stimulant pharmacologic agent areformulated for release according to separate schedules. In someembodiments, the stimulant pharmacologic agent is formulated to beginrelease upon administration to a subject. In some embodiments, thestimulant pharmacologic agent is formulated to release over the courseof 0.15 (or less) to 6 hours (e.g., 0.15-6 hours, 0.1-5 hours, 0.15-2hours, 0.15-3 hours, 0.15-4 hours, 0.5-6 hours, etc.), although theinvention is not limited to this particular range. In some embodiments,all or a portion of the stimulant pharmaceutical agent is coated forenteric release. In some embodiments, the non-stimulant pharmacologicagent is formulated to release over the course of 0.15 to 14 (e.g.,0.15-14 hours, 0.3-14 hours, 0.3-12 hours, 0.5-10 hours, 0.5-14 hours,0.15-8 hours, etc.), although the invention is not limited to thisparticular range. In some embodiments, the non-stimulant pharmacologicagent is formulated to begin release upon administration to a subject.In some embodiments, the non-stimulant pharmacologic agent is formulatedfor delayed release. In some embodiments, delayed release comprisesrelease beginning 3 to 6 hours after administration to a subject. Insome embodiments, all or a portion of the non-stimulant pharmaceuticalagent is coated for enteric release. In some such embodiments, after anenteric coating is removed, the non-stimulant is immediately released.In some embodiments, a pharmaceutical composition further comprises anagent to reduce abdominal pain. In some embodiments, the agent to reduceabdominal pain is coated for enteric release. In some embodiments, theagent to reduce abdominal pain comprises peppermint oil.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a stimulant pharmacologic agent for treatment ofADHD, wherein the stimulant pharmacologic agent is provided in ananoparticulate formulation (e.g. for enhanced bioavailability, fastaction, for controlled release, etc.). In some embodiments, the presentinvention provides a pharmaceutical composition comprising anon-stimulant pharmacologic agent for treatment of ADHD, wherein thenon-stimulant pharmacologic agent is provided in a nanoparticulateformulation (e.g. for enhanced bioavailability, for controlled release,etc.). In some embodiments, the present invention provides apharmaceutical composition comprising a stimulant pharmacologic agentfor treatment of ADHD and a non-stimulant pharmacologic agent fortreatment of ADHD, wherein the stimulant pharmacologic agent is providedin a nanoparticulate formulation, wherein the non-stimulantpharmacologic agent is provided in a nanoparticulate formulation, orwherein both the stimulant pharmacologic agent and non-stimulantpharmacologic agent are provided in a nanoparticulate formulation, andwherein the stimulant pharmacologic agent and the non-stimulantpharmacologic agent are formulated for release according to separateschedules. In one or more embodiments, pharmacologic agents administeredin a nanoparticulate formulation are further formulated foradministration via other formulation methods described herein (e.g.co-administration, enteric coating, controlled release, delayed release,immediate release, etc.). In some embodiments, a stimulant pharmacologicagent and/or non-stimulant pharmacologic agent is complexed to one ormore compounds comprising a nanoparticle (e.g. to enhancebioavailability, to provide slower release of therapeutic, etc.). Insome embodiments, a stimulant pharmacologic agents and/or non-stimulantpharmacologic agents are encapsulated within nanoparticles. It iscontemplated that use of nanoparticulate formulations permits furtherreduction in the dosage of one or more active agents to achieve anefficacious dose with fewer or reduced side effects.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a first pharmacologic agent (e.g., stimulant) anda second pharmaceutical agent, wherein the first pharmaceutical agent isformulated as a nanoparticulate and the second pharmaceutical agent isnot formulated as a nanoparticulate. In some embodiments, the firstpharmacologic agent is a stimulant and the second pharmaceutical agentis a non-stimulant. In some embodiments, the first pharmacologic agentis a stimulant and the second pharmaceutical agent is a stimulant. Insome embodiments, the first pharmacologic agent is a non-stimulant andthe second pharmaceutical agent is a non-stimulant. In some embodiments,the first pharmacologic agent and the second pharmaceutical agent arethe same agents (e.g., same pharmaceutical compounds). In someembodiments, the first pharmacologic agent and the second pharmaceuticalagent are formulated differently (e.g., nanoparticulate formulation,slow-release formulation, etc.).

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a first pharmaceutical formulation and a secondpharmaceutical formulation, wherein the first pharmaceutical formulationcomprises one or more pharmaceutical agents formulated as ananoparticulate, and the a second pharmaceutical formulation comprisesone or more pharmaceutical agents formulated for slow-release. In someembodiments, the first pharmaceutical formulation and secondpharmaceutical formulation comprise the same pharmaceutical agents. Insome embodiments, the first pharmaceutical formulation and secondpharmaceutical formulation comprise the different pharmaceutical agents.In some embodiments, the first pharmaceutical formulation comprises oneor more stimulant pharmaceuticals. In some embodiments, the firstpharmaceutical formulation comprises one or more non-stimulantpharmaceuticals. In some embodiments, the second pharmaceuticalformulation comprises one or more stimulant pharmaceuticals. In someembodiments, the second pharmaceutical formulation comprises one or morenon-stimulant pharmaceuticals. In some embodiments, the pharmaceuticalagents in the first formulation are formulated for rapid-release uponadministration to a subject. In some embodiments, the pharmaceuticalagents in the second formulation are formulated for slow-release uponadministration to a subject.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a stimulant pharmaceutical agent formulated as ananoparticulate. In some embodiments, the formulation permits fastaction of the stimulant (e.g., biological activity and/or onset ofabsorption in less than 15 minutes, less than 10 minutes, less than 5minutes, less than 2 minutes) and/or such that activity (and associatedside effects, such as sleeplessness) are diminished after a desirableperiod of time (e.g., before, for example, 10 hours, 8 hours, 6 hours,or 4 hours after administration).

In some embodiments, the present invention provides nanoparticlecompositions comprising one or more pharmaceutical agents (e.g.,stimulant, non-stimulant, etc.). In some embodiments, the presentinvention provides nanoparticle compositions comprising one or morestimulant pharmaceuticals, for example, amphetamine (e.g., Adderall,Adderal XR, Adderal IR, etc.), methylphenidate (e.g., Ritalin, Methylin,Ritalin SR, Metadate ER, Methylin, Methylin ER, Concerta, Metadate CD,Ritalin LA, etc.), dexmethylphanidate (e.g., Focalin, Focalin XR, etc.)(See U.S. Pat. No. 7,431,944, herein incorporated by reference in itsentirety), lisdexamfetamine (e.g., Vyvanse), etc. In some embodiments,pharmaceutical comprise a single enantiomer of a stimulant agnet. Insome embodiments, pharmaceutical nanoparticulates have a diameter (e.g.,mean diameter) of less than about 10 μm (e.g., <10 μm, <5 μm, <2 μm, <1μm, <500 nm, <200 nm, <100 nm, <50 nm, <20 nm, <10 nm, etc.). In someembodiments, a plurality of pharmaceutical nanoparticulates have a meandiameter of less than about 10 μm (e.g., <10 μm, <5 μm, <2 μm, <1 μm,<500 nm, <200 nm, <100 nm, <50 nm, <20 nm, <10 nm, etc.). In someembodiments, pharmaceutical nanoparticulates have a diameter (e.g., meandiameter) of about 500 nm. In some embodiments, pharmaceuticalnanoparticulates have a diameter (e.g., mean diameter) of about 400 nm.In some embodiments, pharmaceutical nanoparticulates have a diameter(e.g., mean diameter) of about 300 nm. In some embodiments,pharmaceutical nanoparticulates have a diameter (e.g., mean diameter) ofabout 200 nm. In some embodiments, pharmaceutical nanoparticulates havea diameter (e.g., mean diameter) of about 100 nm. In some embodiments,pharmaceutical nanoparticulates have a diameter (e.g., mean diameter) ofabout 100-500 nm.

In some embodiments, methods are provided for the production ofpharmaceutical nanoparticles. In some embodiments, pharmaceuticalnanoparticles are produced through one or more steps, including, but notlimited to milling and drying. In some embodiments, milling comprisesroller milling, spindle milling, or any suitable alternative (e.g.,other form of milling, alternative to milling, etc.). In someembodiments, milling of one or more pharmaceutical agents is performedin the presence of one or more solvents (e.g., milling vehicles). Insome embodiments, suitable solvents for milling minimize salvation ofthe pharmaceutical agent(s). In some embodiments, suitable solvents formilling are volatile. In some embodiments, suitable solvents for millinginclude, but are not limited to ethyl acetate, methylene chloride,hexanes, and cyclomethicone. Methods of making nanoparticulatecompositions are described in U.S. Pat. No. 5,518,187 for “Method ofGrinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388 for“Continuous Method of Grinding Pharmaceutical Substances;” U.S. Pat. No.5,862,999 for “Method of Grinding Pharmaceutical Substances;” U.S. Pat.No. 5,665,331 for “Co-Microprecipitation of NanoparticulatePharmaceutical Agents with Crystal Growth Modifiers;” U.S. Pat. No.5,662,883 for “Co-Microprecipitation of Nanoparticulate PharmaceuticalAgents with Crystal Growth Modifiers;” U.S. Pat. No. 5,560,932 for“Microprecipitation of Nanoparticulate Pharmaceutical Agents;” U.S. Pat.No. 5,543,133 for “Process of Preparing X-Ray Contrast CompositionsContaining Nanoparticles;” U.S. Pat. No. 5,534,270 for “Method ofPreparing Stable Drug Nanoparticles;” U.S. Pat. No. 5,510,118 for“Process of Preparing Therapeutic Compositions ContainingNanoparticles;” and U.S. Pat. No. 5,470,583 for “Method of PreparingNanoparticle Compositions Containing Charged Phospholipids to ReduceAggregation,” all of which are specifically incorporated by reference.In some embodiments, drying of a pharmaceutical composition of thepresent invention is performed by any suitable method (e.g., air drying,vacuum drying, lyophilization, etc.). In some embodiments, milling andor drying is followed by one or more additional steps including but notlimited to sonication.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising an agent to deter abuse of said pharmaceuticalcomposition. In some embodiments, an agent to deter abuse comprises anasal and/or mucosal irritant, polymer composition, and/or emeticcompound.

In some embodiments, the present invention provides method of treatingADHD (or a similar psychiatric condition or a condition exhibitingsimilar symptoms) in a subject by administering a pharmaceuticalcomposition comprising a nanoparticulate formulation of l-amphetamineand d-amphetamine. In some embodiments, the present invention providesmethod of treating ADHD (or a similar psychiatric condition or acondition exhibiting similar symptoms) in a subject by administering apharmaceutical composition comprising a nanoparticulate formulation ofamphetamine (e.g., Adderall). In some embodiments, the present inventionprovides method of treating ADHD (or a similar psychiatric condition ora condition exhibiting similar symptoms) in a subject byco-administering: (a) a pharmaceutical composition comprising ananoparticulate formulation of l-amphetamine and d-amphetamine, and (b)a second pharmaceutical agent to the subject. In some embodiments, thepresent invention provides method of treating ADHD (or a similarpsychiatric condition or a condition exhibiting similar symptoms) in asubject by co-administering: (a) a pharmaceutical composition comprisinga nanoparticulate formulation of amphetamine (e.g., Adderall), and (b) asecond pharmaceutical agent to the subject. In some embodiments, thesecond pharmaceutical agent is formulated for delayed release. In someembodiments, the second pharmaceutical agent is coated for entericrelease. In some embodiments, the second pharmaceutical agent is anon-stimulant. In some embodiments, the non-stimulant is selected fromAtomoxetine, Guanfacine, and Clonidine. In some embodiments, the secondpharmaceutical agent is a stimulant.

In some embodiments, the present invention provides a method forproducing a nanoparticulate formulation of l-amphetamine andd-amphetamine comprising: (a) forming a mixture of l-amphetamine,d-amphetamine, and one or more vehicles; (b) milling said mixture; and(c) drying said mixture. In some embodiments, the present inventionprovides a method for producing a nanoparticulate formulation ofamphetamine (e.g., Adderall) comprising: (a) forming a mixture ofamphetamine (e.g., Adderall) and one or more vehicles; (b) milling saidmixture; and (c) drying said mixture. In some embodiments, thenanoparticles produced have a mean nanoparticle diameter of less than500 nm. In some embodiments, the nanoparticles produced have a meannanoparticle diameter of less than 250 nm.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a first nanoparticulate formulation and a secondnon-nanoparticulate formulation, wherein the nanoparticulate formulationcomprises one or more stimulants and the non-nanoparticulate formulationcomprises one or more non-stimulant pharmaceutical agents. In someembodiments, the one or more stimulants comprise l-amphetamine andd-amphetamine. In some embodiments, the one or more stimulants comprisesAdderall. In some embodiments, the one or more stimulants comprisesFocalin. In some embodiments, the mean nanoparticle diameter of thenanoparticulate formulation is less than 500 nm. In some embodiments,the mean nanoparticle diameter of the nanoparticulate formulation isless than 250 nm. In some embodiments, one of the one or morenon-stimulants and selected from Atomoxetine, Guanfacine, and Clonidine.

In some embodiments, nanoparticulate formulations provide rapid releaseof a therapeutic (e.g., stimulant, amphetamine, Adderall, Focalin,etc.). In some embodiments, nanoparticulate formulations provideimmediate release of a therapeutic (e.g., stimulant, amphetamine,Adderall, etc.). In some embodiments, rapid and/or immediate release ofa therapeutic into a subject in less than 1 hour after administration(e.g., <1 hour . . . <30 minutes . . . <15 minutes . . . <10 minutes . .. <5 minutes . . . <1 minute, or faster). In some embodiments, rapidand/or immediate release of a therapeutic into a subject in less than 30minutes after administration (e.g., <30 minutes . . . <15 minutes . . .<10 minutes . . . <5 minutes . . . <1 minute, or faster). In someembodiments, rapid and/or immediate release of a therapeutic into asubject in less than 15 minutes after administration (e.g., <15 minutes. . . <10 minutes . . . <5 minutes . . . <1 minute, or faster). In someembodiments, nanoparticulate formulations are configured for dissolvingin the mouth (e.g., tablet, strip, gel, etc.) and provide rapid drug(e.g., stimulant, amphetamine, Adderall, Focalin, etc.) release into theoral mucosa. In some embodiments, nanoparticulate formulationsconfigured for fast onset dose (e.g., when fast onset is necessary, inaddition to current therapy where control of symptoms, disorder,disease, condition, etc. (e.g., ADHD) is insufficient, etc.). In someembodiments, nanoparticulate formulations of stimulant or non-stimulantprovide very fast drug release (e.g., <30 minutes, <15 minutes, or less)and absorption compared to the non-nanoparticulate formulations. In someembodiments, nanoparticulate formulations of stimulant or non-stimulantare administered with a suitable slow release component to provide oncedaily dosing. In some embodiments, a stimulant or non-stimulantnanoparticulate formulation is coadministered in a 0.1 to 50% mixturewith non-nanoparticulate slow release formulation. In some embodiments,a nanoparticulate formulation allows for lower dosing compared tonon-nanoparticulate formulations. In some embodiments, nanoparticulateformulations are provided with particle size below 1000 micron.

In some embodiments, the present invention provides pharmaceuticalcompositions comprising a nanoparticulate formulation of a stimulantpharmacologic agent. In some embodiments, the stimulant pharmacologicagent is formulated to begin release upon administration to a subject.In some embodiments, the stimulant pharmacologic agent is formulated forrelease within 30 minutes of administration. In some embodiments, thestimulant pharmacologic agent is formulated for release within 15minutes of administration. In some embodiments, the stimulantpharmacologic agent is formulated to begin immediate release uponadministration to a subject. In some embodiments, the stimulantpharmacologic agent is selected from amphetamines, lisdexamphetamines,methylphenidates, dexmethylphenidates, and dexamphetamines. In someembodiments, the nanoparticulate formulation comprises particles of lessthan 1000 microns in diameter (e.g., <500 nm, <250 nm, <100 nm). In someembodiments, the particles in said nanoparticulate formulation are allless than 1000 microns in diameter (e.g., <500 nm, <250 nm, <100 nm). Insome embodiments, the pharmaceutical composition is provided in a dosageas a tablet, capsule, orally-disintegrating formulation, pill, powder,solution, elixir, syrup, suspension, lozenge, or spray. In someembodiments, the pharmaceutical composition comprises an orallydisintegrating tablet formulation. In some embodiments, the presentinvention provides a method of treating a disease, disorder, orcondition by administering a pharmaceutical composition comprising arapid-release nanoparticulate formulation of a stimulant pharmacologicagent.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a rapid-release nanoparticulate formulation of astimulant pharmacologic agent and a non-nanoparticulate formulatedtherapeutic. In some embodiments, the stimulant pharmacologic agent isselected from amphetamines, lisdexamphetamines, methylphenidates,dexmethylphenidates, and dexamphetamines In some embodiments, thenon-nanoparticulate formulated therapeutic is a stimulant. In someembodiments, the non-nanoparticulate formulated therapeutic is selectedfrom amphetamines, lisdexamphetamines, methylphenidates,dexmethylphenidates, and dexamphetamines. In some embodiments, thenon-nanoparticulate formulated therapeutic is a non-stimulant. In someembodiments, the non-nanoparticulate formulated therapeutic is anon-stimulant selected from Atomoxetine, Guanfacine, and Clonidine. Insome embodiments, the non-stimulant pharmacologic agent is formulatedfor delayed release. In some embodiments, the non-stimulantpharmacologic agent is formulated for slow release. In some embodiments,the non-stimulant pharmacologic agent is coated for enteric release. Insome embodiments, the composition is provided in a dosage as a tablet,capsule, orally-disintegrating tablets, pill, powder, solution, elixir,syrup, suspension, lozenge, or spray. In some embodiments, the presentinvention provides a method of treating a disease, disorder, orcondition by administering a pharmaceutical composition comprising arapid-release nanoparticulate formulation of a stimulant pharmacologicagent and a non-nanoparticulate formulated therapeutic.

In some embodiments, the present invention provides pharmaceuticalcompositions comprising dose of a stimulant pharmacologic agent that is20% lower than a standard dose for the stimulant, wherein the stimulantpharmacologic agent is formulated as a nanoparticulate, wherein thepharmaceutical composition is formulated as a orally disintegratingtablet, and wherein onset of therapeutic action of the stimulantpharmacologic agent is within 30 minutes of oral administration to asubject.

In some embodiments, the present invention provides methods of treatingattention deficit hyperactive disorder by administering a pharmaceuticalcomposition comprising dose of a stimulant pharmacologic agent that is20% lower than a standard dose for the stimulant, wherein the stimulantpharmacologic agent is formulated as a nanoparticulate, wherein thepharmaceutical composition is formulated as a orally disintegratingtablet, and wherein onset of therapeutic action of the stimulantpharmacologic agent is within 30 minutes of oral administration to asubject.

In some embodiments, the present invention provides controlledsequential-release pharmaceutical compositions comprising: (a) a 50%lower than standard dose of a stimulant pharmacologic agent, wherein thestimulant pharmacologic agent is formulated as a nanoparticulate,wherein onset of therapeutic action of the stimulant pharmacologic agentis within 30 minutes of oral administration to a subject, and whereintherapeutic levels of the stimulant pharmacologic agent are maintainedin the subject for 8 hours post; and (b) 50% lower than standard dose ofa non-stimulant therapeutic agent, wherein the non-stimulant therapeuticagent is formulated for release 4 hours post-administration to thesubject, and wherein therapeutic levels of the non-stimulant therapeuticagent are maintained in the subject for 8 hours.

In some embodiments, the present invention provides methods of treatingattention deficit hyperactive disorder by administering a controlledsequential-release pharmaceutical compositions comprising: (a) a 50%lower than standard dose of a stimulant pharmacologic agent, wherein thestimulant pharmacologic agent is formulated as a nanoparticulate,wherein onset of therapeutic action of the stimulant pharmacologic agentis within 30 minutes of oral administration to a subject, and whereintherapeutic levels of the stimulant pharmacologic agent are maintainedin the subject for 8 hours post; and (b) 50% lower than standard dose ofa non-stimulant therapeutic agent, wherein the non-stimulant therapeuticagent is formulated for release 4 hours post-administration to thesubject, and wherein therapeutic levels of the non-stimulant therapeuticagent are maintained in the subject for 8 hours.

In some embodiments, the present invention provides administration to ortreatment of pediatric subjects (e.g., 0-19 years), infant subjects(e.g., 0-2), children (e.g., 2-12 years), adolescent subjects (e.g.,13-19 years), and/or adult subjects (e.g., 20+ years).

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a nanoparticulate formulation of l-amphetamineand d-amphetamine. In some embodiments, a pharmaceutical compositioncomprises a nanoparticulate formulation of Adderall. In someembodiments, a pharmaceutical composition comprises a nanoparticulateformulation of Focalin. In some embodiments, the mean nanoparticlediameter of the nanoparticulate formulation is less than orapproximately 500 nm. In some embodiments, the mean nanoparticlediameter of the nanoparticulate formulation is less than orapproximately 250 nm.

In some embodiments, pharmaceutical compositions comprisingnanoparticulate formulations and/or non-nanoparticulate formulations areutilized in solid or liquid dosage formulations, such as liquiddispersions, gels, aerosols, ointments, creams, controlled releaseformulations, fast melt formulations, lyophilized formulations, tablets,capsules, rapid-release formulations, delayed release formulations,extended release formulations, pulsatile release formulations, mixedimmediate release and controlled release formulations, etc.

In some embodiments, the present invention provides pharmaceuticalcomposition comprising a nanoparticulate formulation of a stimulantpharmacologic agent. In some embodiments, the stimulant pharmacologicagent is formulated to begin release upon administration to a subject.In some embodiments, the stimulant pharmacologic agent is formulated forrelease within 30 minutes. In some embodiments, the pharmaceuticalcomposition comprises 20% less stimulant pharmacologic agent thanstandard stimulant pharmacologic formulations. In some embodiments, thestimulant pharmacologic agent is formulated to begin release uponadministration to a subject. In some embodiments, the stimulantpharmacologic agent is selected from amphetamines, lisdexamphetamines,methylphenidates, dexmethylphenidates, and dexamphetamines. In someembodiments, the nanoparticulate formulation comprises particles of lessthan 1000 microns in diameter. In some embodiments, the particles in thenanoparticulate formulation are all less than 1000 microns in diameter.In some embodiments, the pharmaceutical composition further comprises anon-nanoparticulate formulation of the stimulant pharmacologic agent.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a stimulant pharmacologic agent and anon-stimulant pharmacologic agent. In some embodiments, the stimulantpharmacologic agent is formulated as a nanoparticulate. In someembodiments, the non-stimulant pharmacologic agent is formulated as ananoparticulate. In some embodiments, the stimulant pharmacologic agentis selected from amphetamines, lisdexamphetamines, methylphenidates,dexmethylphenidates, and dexamphetamines. In some embodiments, thenon-stimulant is selected from Atomoxetine, Guanfacine, and Clonidine.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a nanoparticulate formulation of a stimulantpharmacologic agent and a non-nanoparticulate formulated therapeutic. Insome embodiments, the stimulant pharmacologic agent is selected fromamphetamines, lisdexamphetamines, methylphenidates, dexmethylphenidates,and dexamphetamines. In some embodiments, the non-nanoparticulateformulated therapeutic is selected from amphetamines,lisdexamphetamines, methylphenidates, dexmethylphenidates,dexamphetamines, Atomoxetine, Guanfacine, and Clonidine. In someembodiments, the non-nanoparticulate formulated pharmacologic agent isformulated for delayed release. In some embodiments, the nanoparticulateformulation of a stimulant pharmacologic agent is formulated forimmediate and/or rapid release. In some embodiments, the pharmaceuticalcomposition comprises reduced doses of the stimulant pharmacologic agentand the non-nanoparticulate formulated therapeutic compared to standardformulations (e.g., once-daily formulations).

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a once-daily fixed-dose sequential-releaseformulation of a stimulant and non-stimulant. In some embodiments, thestimulant is selected from one or more of amphetamines,lisdexamphetamines, methylphenidates, dexmethylphenidates, anddexamphetamines. In some embodiments, all or a portion of the stimulantis nanoparticulate formulated. In some embodiments, all or a portion ofthe stimulant is not nanoparticulate formulated. In some embodiments,all or a portion of the stimulant is formulated for immediate release.In some embodiments, all or a portion of the stimulant is formulated fordelayed release. In some embodiments, the non-stimulant is selected fromone or more of Atomoxetine, Guanfacine, and Clonidine. In someembodiments, all or a portion of the non-stimulant is nanoparticulateformulated. In some embodiments, all or a portion of the non-stimulantis not nanoparticulate formulated. In some embodiments, all or a portionof the non-stimulant is formulated for immediate release. In someembodiments, all or a portion of the non-stimulant is formulated fordelayed release.

In some embodiments, the present invention provides methods of treatingattention deficit hyperactive disorder in a subject by administering tothe subject a pharmaceutical composition described herein. In someembodiments, the subject is a child, adolescent, or adult. In someembodiments, the dose of the stimulant at least 10% less than a standardadministered dose of the stimulant. In some embodiments, the subjectexperiences reduced side effects compared to a standard administereddose of the stimulant. In some embodiments, the reduced side effectsinclude one or more of: changes in appetite, sleep loss, tics,slowed/reduced growth, or combinations thereof. In some embodiments,formulations prevent or reduce such side effects, e.g., due to lowerdose or other mechanisms—the present invention is not limited to anyparticular mechanism of action and an understanding of the mechanism ofaction is not necessary to practice the present invention.

In some embodiments, the present invention provides pharmaceuticalcompositions comprising a stimulant pharmaceutical agent and a secondpharmaceutical agent, wherein the stimulant pharmaceutical agent isformulated for release at two distinct time-points followingadministration to a subject. In some embodiments, the stimulantpharmaceutical agent is selected from one or more of amphetamines,lisdexamphetamines, methylphenidates, dexmethylphenidates, anddexamphetamines. In some embodiments, all or a portion of the stimulantpharmaceutical agent is nanoparticulate formulated. In some embodiments,a first portion of the stimulant pharmaceutical agent is formulated forimmediate release and a second portion of the stimulant pharmaceuticalagent is formulated for delayed release. In some embodiments, the secondpharmaceutical agent is selected from one or more of amphetamines,lisdexamphetamines, methylphenidates, dexmethylphenidates,dexamphetamines, Atomoxetine, Guanfacine, and Clonidine. In someembodiments, all or a portion of the second pharmaceutical agent isnanoparticulate formulated. In some embodiments, all or a portion of thesecond pharmaceutical agent is formulated for delayed release. In someembodiments, administration of the pharmaceutical composition to asubject results in three or more peaks of pharmaceutical release (e.g.,3 peaks, 4 peaks, 5 peaks, 6 peaks, or more).

In some embodiments, the present invention provides compositions andmethods for improving the quality of life (QOL) of a patient with ADHDwhere the QOL comprising multidimensional aspects of well being, social,emotional, family, functional and concerns for patients on stimulanttherapy such as weight loss and insomnia. In some embodiments, theimprovement in CHIP score from baseline is greater than 1%(e.g., >2%, >3%, >4%, >5%, >6%, >7%, >8%, >9%, >10%, or more). Forexample in some embodiments, a method of treating a subject for ADHDsymptoms is provided comprising administering dose of stimulant in themorning and a dose of non-stimulant in the afternoon to reduce sideeffects and improve quality of life over stimulant-only therapies.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows laser scattering particle size distribution analysis ofamphetamine salts prior to milling.

FIG. 2 shows laser scattering particle size distribution analysis ofamphetamine in ethyl acetate, 0.5% oleic acid, and cyclohexane.

FIG. 3 shows photomicrograph of amphetamine in ethyl acetate, 0.5% oleicacid, and cyclohexane.

FIG. 4 shows laser scattering particle size distribution analysis ofamphetamine 0.5% oleic acid and cyclohexane after 30 minutes of milling.

FIG. 5 shows photomicrograph of amphetamine in 0.5% oleic acid andcyclohexane after 30 minutes of milling.

FIG. 6 shows laser scattering particle size distribution analysis ofamphetamine 0.5% oleic acid and cyclohexane after 60 minutes of milling.

FIG. 7 shows photomicrograph of amphetamine in 0.5% oleic acid andcyclohexane after 60 minutes of milling.

FIG. 8 shows laser scattering particle size distribution analysis ofamphetamine 0.5% oleic acid and cyclohexane after 120 minutes ofmilling.

FIG. 9 shows photomicrograph of amphetamine in 0.5% oleic acid andcyclohexane after 120 minutes of milling.

FIG. 10 shows laser scattering particle size distribution analysis ofamphetamine 0.5% oleic acid and cyclohexane after 240 minutes ofmilling.

FIG. 11 shows photomicrograph of amphetamine in 0.5% oleic acid andcyclohexane after 240 minutes of milling.

FIG. 12 shows laser scattering particle size distribution analysis ofamphetamine 0.5% Sedefos 75 and cyclohexane after 240 minutes ofmilling.

FIG. 13 shows photomicrograph of amphetamine in Sedefos 75 andcyclohexane after 240 minutes of milling.

FIG. 14 shows laser scattering particle size distribution analysis ofamphetamine in ethanol after 40 hours of milling.

FIG. 15 shows photomicrograph of amphetamine in Sedefos 75 andcyclohexane after 40 hours of milling.

FIG. 16 shows laser scattering particle size distribution analysis ofamphetamine in ethanol after 40 hours of milling: before drying (mediansize=170 nm), dried under vacuum and 10 min. sonication (mediansize=2.91 μm), and dried under vacuum and 30 sec. sonication (mediansize=1.63 μm).

FIG. 17 shows laser scattering particle size distribution analysis ofamphetamine in ethanol after 40 hours of milling, before and afterlyophilization with PVP cryoprotectant.

DEFINITIONS

As used herein, the term “co-administration” refers to theadministration of at least two agent(s) (e.g., a compound of the presentinvention) or therapies to a subject. In some embodiments, theco-administration of two or more agents/therapies is concurrent. Inother embodiments, the co-administration of two or more agents/therapiesis sequential (e.g., a first agent/therapy is administered prior to asecond agent/therapy). In some embodiments, the two or more therapiesare administered concurrently, but released (e.g., absorbed, becomebioavailable, etc.) sequentially. For example, a composition comprisinga first agent and a second agent is administered to a subject (e.g.,orally), the first agent is released and becomes bioavailableimmediately, but the second agent is formulated for delayed release(e.g., enteric release, release 2-8 hours after administration, etc.).Those of skill in the art understand that the formulations and/or routesof administration of the various agents/therapies used may vary. Theappropriate dosage for co-administration can be readily determined byone skilled in the art. In some embodiments, when agents/therapies areco-administered, the respective agents/therapies are administered atlower dosages than appropriate for their administration alone. Thus,co-administration is especially desirable in embodiments where theco-administration of the agents/therapies lowers the requisite dosage ofa known potentially harmful (e.g., toxic) agent(s).

The term “therapeutically effective amount” means an amount of a drugeffective to facilitate a desired therapeutic effect in a particularclass of subject (e.g., infant, child, adolescent, adult). As usedherein, the term “subtherapeutic” refers to an amount of apharmaceutical agent that is insufficient to achieve the desired and/oranticipated therapeutic result/outcome upon administration to an averageand/or typical subject (e.g., average size, taking no contraindicatedpharmaceutical agents, having a similar reaction to the dose as amajority of the population, etc.). A subtherapeutic dose may be agedependent (e.g., infant, child, adolescent, adult). U.S. Food and DrugAdministration (FDA) recommended dosages are indicative of therapeuticdose, and may be used to inform the determination of a subtherapeuticdose.

As used herein, the term “once-daily” refers to a pharmaceutical that isformulated for administration to a subject one time per day. Thepharmaceutical may provide the therapeutic result for a full 24 hours,or may provide treatment for only a desired/anticipated fraction thereof(e.g., 8 hours, 10 hours, 12, hours, 16 hours), depending upon theintended function of the pharmaceutical. In cases where a once-dailydose provides less than 24 hours of therapeutic action, the duration ofaction achieved is the desired time span and re-administration in thesame 24 hour period is not required. Due to the side effects of apharmaceutical (e.g., insomnia), it may be desired/beneficial for thetherapeutic action of a once-daily dose to last less than 24 hours(e.g., 8 hours, 10 hours, 12, hours, 16 hours)

As used herein, the term “pharmaceutical agent” refers to a compound,macromolecule, or other entity that is administered (e.g., within thecontext of a pharmaceutical composition) to a subject to elicit adesired biological response. A pharmaceutical agent may be a “drug” orany other material which is biologically active in a human being orother mammal, locally and/or systemically. Examples of drugs aredisclosed in the Merck Index and the Physicians Desk Reference, theentire disclosures of which are incorporated by reference herein for allpurposes.

As used herein, the term “pharmaceutical formulation” refers to at leastone pharmaceutical agent in combination with one or more additionalcomponents that assist in rendering the pharmaceutical agent(s) suitablefor achieving the desired effect upon administration to a subject. Thepharmaceutical formulation may include one or more additives, forexample pharmaceutically acceptable excipients, carriers, penetrationenhancers, coatings, stabilizers, buffers or other materials physicallyassociated with the pharmaceutical agent to enhance the administration,release (e.g., timing of release), deliverability, bioavailability,effectiveness, etc. of the dosage form. The formulation may be, forexample, a liquid, a suspension, a solid, a nanoparticle, emulsion,micelle, ointment, gel, emulsion, coating, etc. A pharmaceuticalformulation (e.g., enteric coated formulation) may contain a singlepharmaceutical agent (e.g., stimulant) or multiple pharmaceutical agents(e.g., stimulant and non-stimulant). A pharmaceutical composition maycontain a single pharmaceutical formulation (e.g., nanoparticulateformulation, etc.) or multiple pharmaceutical formulations (e.g., afirst immediate release nanoparticulate formulation and a seconddelayed-release enterically-coated formulation, etc.).

As used herein, the term “pharmaceutical composition” refers to thecombination of one or more pharmaceutical agents with one or morecarriers, inert or active, making the composition especially suitablefor diagnostic or therapeutic use in vivo, in vivo or ex vivo. Apharmaceutical composition comprises the physical entity that isadministered to a subject, and may take the form of a solid, semi-solidor liquid dosage form, such as tablet, capsule, orally-disintegratingtablet, pill, powder, suppository, solution, elixir, syrup, suspension,cream, lozenge, paste, spray, etc. A pharmaceutical composition maycomprise a single pharmaceutical agent or multiple pharmaceuticalagents. A pharmaceutical composition may comprise a singlepharmaceutical formulation (e.g., extended release, immediate release,delayed release, nanoparticulate, etc.) or multiple formulations (e.g.,immediate release and delayed release, nanoparticulate andnon-nanoparticulate, etc.).

As used herein, the term “sequential release” refers to a releaseprofile for a pharmaceutical composition in which a two or morepharmaceutical agents are released (e.g., from a nanoparticulate, froman enteric coating, etc.) at distinct time points followingadministration to a subject. The release timepoint may refer to thepharmaceutical agent being absorbed by a subject, entering the bloodstream, becoming bioavailable, etc. the time interval between releasetimepoints may be measured from initial release or from the peak releaseof each pharmaceutical agent. Pharmaceutical agents may have overlapbetween their release profiles (e.g., 0-4 hours and 2-5 hours) and stillbe considered sequential release if they exhibit distinct onsets ofrelease or peaks of release. A time interval of about 1 hour istypically required to constitute sequential release. The term“concurrent release” refers to pharmaceutical agents with substantiallyidentical release profiles, onsets of release, and/or peak releases.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants. (See e.g., Martin,Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton,Pa. [1975]).

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfinuric, nitric,perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic,succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides drug therapy formulations. In someembodiments, the present invention provides drug combinations (e.g.,co-administrations), formulations (e.g., nanoparticulate,non-nanoparticulate), release profiles (e.g., immediate release, delayedrelease, sustained release, and combinations thereof), and combinationsthereof to provide therapeutic benefit with reduced side effects. Insome embodiments, the present invention provides drug therapyformulations (e.g., nanoparticulate formulations, rapid-releaseformulations, rapid-clearance formulations, delayed releaseformulations, mixed immediate release and controlled releaseformulations, etc.). In some embodiments, provided herein arepharmaceutical formulations for reducing the side effects associatedwith a therapeutic (e.g., stimulant (e.g., Focalin, Adderall)). In someembodiments, the present invention provides a reduction in side effects(e.g., sleep- and/or diet-related side effects) associated with atherapeutic (e.g., stimulant (e.g., Adderall, Focalin)). In someembodiments, the present invention provides drug formulations (e.g.,nanoparticulate formulation, co-administration, release profiles, etc.)for enhanced benefit (e.g., rapid release, rapid clearance, rapid onsetof therapeutic effect, reducing the side effects, etc.) of a therapeutic(e.g., stimulant (e.g., Adderall, Focalin)). In some embodiments, thepresent invention provides a reduction in sleep- and diet-related sideeffects associated with a first therapeutic (e.g., stimulant) throughco-administration with a time-released second therapeutic,nanoparticulate formulation, varied release profiles (e.g., immediaterelease, delayed release, etc.), and combinations thereof. In someembodiments, the present invention provides formulations (e.g.,nanoparticulate formulation, co-administration, release profiles,combinations thereof, etc.) of one or more therapeutics which allowstherapeutic benefit with reduced dosage, thereby reducing side effects(e.g. sleep- and diet-related side effects). In some embodiments, thepresent invention provides formulations (e.g., nanoparticulateformulation, co-administration, release profiles, combinations thereof,etc.) which provide enhanced bioavailability, thereby reducingassociated side effects (e.g. sleep- and diet-related side effects). Insome embodiments, the present invention provides formulations (e.g.,nanoparticulate formulation, co-administration, release profiles,combinations thereof, etc.) which provide rapid bioavailability. In someembodiments, the present invention provides formulations (e.g.,nanoparticulate formulation, co-administration, release profiles,combinations thereof, etc.) which provide rapid clearance from the blood(e.g., thereby reducing associated side effects (e.g. sleep- anddiet-related side effects)).

In some embodiments, the present invention provides compositions andmethods for treatment and/or symptom reduction of attention deficitdisorder (ADD), attention deficit hyperactive disorder (ADHD), adultADD, adult ADHD, pediatric ADD, pediatric ADHD, and related conditionsand/or disorders. All embodiments of the invention described herein canbe applied to the above conditions and/or disorders. In someembodiments, the present invention provides a method of treating,preventing, or ameliorating signs or symptoms of a disease or conditionin a subject. To illustrate aspects of the invention, the remainingdescription focuses on ADHD (attention deficit hyperactivity disorder).However, it should be understood that the invention is not limited tothis particular condition. In some embodiments, the present inventionprovides treatment and/or symptom reduction for: ADHD, one or moresymptoms of ADHD, ADHD-like conditions, psychiatric side effects ofother pharmaceuticals, psychiatric conditions, conditions presenting oneor more symptoms of ADHD, attention deficit disorder (ADD), bipolardisorder, autism, seizure disorders, etc. It will be understood that theformulations (e.g., nanoparticulate formulation, drug co-administration,varied release profiles, and combinations thereof) find use in thetreatment of such diseases, conditions, and disorders as well.Pharmaceutical compositions and formulations for the treatment of suchother conditions are within the scope of the present invention.

Some embodiments of the present invention provide enhanced efficacyinstead of, or in addition to, reduced side effects. In someembodiments, pharmaceutical compositions are provided that compriseconventional therapeutic doses in the pharmaceutical formulationsdescribed herein (e.g., sequential release, nanoparticulate,co-administration). Therefore, while possibly also achieving a reductionin side effects, the formulations provide enhanced efficacy,bioavailabilty, onset of action, duration, etc. compared to conventionaltherapeutic doses in standard formulations. In some embodiments, reduceddose formulations (e.g., subtherapeutic) provide enhanced efficacy inthe formulations described herein.

A. Stimulant

In some embodiments, stimulant pharmaceuticals for use with the presentinvention include amphetamines (e.g. Adderall XR, Adderall, etc.),lisdexamphetamine (e.g. Vyvanse, etc.), methylphenidate (e.g. Concerta,Ritalin, Ritalin LA, Metadate CD, Metadate ER, etc.), dexmethylphenidate(e.g. Focalin, Focalin XR, etc.), and dexamphetamine (e.g. Dexedrine).Those of skill in the will recognize that this list is not limiting andrecognize additional stimulant pharmaceuticals which will find use withembodiments of the present invention.

In certain embodiments, stimulant pharmaceuticals are formulatedaccording to any embodiments described herein, for example:nanoparticulate formulation, non-nanoparticulate formulation, combinednanoparticulate/non-nanoparticulate formulation, immediate release,delayed release, sustained release, co-administration (e.g., with one ormore non-stimulants, with one or more additional stimulants), anysuitable combinations thereof, etc.

In some embodiments, the stimulant pharmaceutical agent is an agent thatincreases the levels of dopamine or norepinephrine in a treated subject.In some embodiments, the non-stimulant pharmaceutical agent is an α2adrenergic agonist. Stimulant pharmacologic agents include, but are notlimited to, any one or more of amphetamines (e.g.,(±)-1-phenylpropan-2-amine), lisdexamphetamines (e.g.,N-[(1S)-1-methyl-2-phenylethyl]-L-lysinamide), methylphenidates (e.g.,methyl phenyl(piperidin-2-yl)acetate), dexmethylphenidates (e.g.,(R,R)-(+)-Methyl 2-phenyl-2-(2-piperidyl)acetate), and dexamphetamines(e.g., (S)-1-phenylpropan-2-amine), or derivatives thereof. In someembodiments, the stimulant pharmacologic agent is selected fromamphetamines (e.g. Adderall XR, Adderall, etc.), lisdexamphetamines(e.g. Vyvanse, etc.), methylphenidates (e.g. Concerta, Ritalin, RitalinLA, Metadate CD, Metadate ER, etc.), dexmethylphenidates (e.g. Focalin,Focalin XR, etc.), and dexamphetamines (e.g. Dexedrine). In someembodiments, the non-stimulant pharmacologic agents include, but are notlimited to, Atomoxetine((3R)—N-methyl-3-(2-methylphenoxy)-3-phenyl-propan-1-amine;(R)—N-methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine), Guanfacine(N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide), and Clonidine(N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine) or derivativesthereof. In some embodiments, a stimulant is a pro-drug (e.g.,lisdeamfetamine). In some embodiments, the non-stimulant pharmacologicagent is selected from Atomoxetine (e.g. Strattera, etc.), Guanfacine(e.g. Intuniv, etc.), Clonidine, etc. In some embodiments, anon-stimulant agent is a slow release formulation (e.g., Intuniv).

In some embodiments, the stimulant Adderall (or another stimulant) isadministered to subjects (e.g., subjects suffering from ADHD). In someembodiments, Adderall is administered in any suitable formulation (e.g.,delayed release, immediate release, enteric coating, nanoparticulate,non-nanoparticulate, combinations thereof, etc.). In some embodiments,the present invention provides formulations of Adderall at doses of lessthan 100 mg/day (e.g., <50 mg/day, <40 mg/day, <30 mg/day, <20 mg/day,<10 mg/day, <5 mg/day, etc.). In some embodiments, a single dose ofAdderall is given each day (e.g., 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4mg, 3 mg, 2 mg, 1 mg, 0.5 mg, 0.1 mg, or doses therein). In someembodiments, multiple doses (e.g., 2, 3, 4, 5, 6, or more) of Adderallare given each day. In some embodiments, individual does contain 10 orless mg/does (e.g., 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2mg, 1 mg). In some embodiments, standard benefit (e.g., reduced ADHDsymptoms) is achieved with a reduced dose of Adderall (e.g., <40 mg/day,<30 mg/day, <20 mg/day, <10 mg/day, <5 mg/day, etc.). In someembodiments, a single reduced dose (e.g., 9 mg, 8 mg, 7 mg, 6 mg, 5 mg,4 mg, 3 mg, 2 mg, 1 mg) is given each day.

In some embodiments, the present invention provides formulations of MPH(e.g., nanoparticulate formulations, non-nanoparticulate formulations,combinations thereor) at doses of less than 100 mg/day (e.g., <50mg/day, <40 mg/day, <30 mg/day, <20 mg/day, <10 mg/day, <5 mg/day,etc.). In some embodiments, a single dose of MPH is given each day(e.g., 18 mg, 17 mg, 16 mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9mg, 8 mg, 7 mg, 6 mg, 5 mg, or less). In some embodiments, multipledoses (e.g., 2, 3, 4, 5, 6, or more) of MPH are given each day. In someembodiments, individual does contain 10 or less mg/does (e.g., 10 mg, 9mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg). In someembodiments, standard benefit (e.g., reduced ADHD symptoms) is achievedwith a reduced dose of MPH (e.g., <20 mg/day, <10 mg/day, <5 mg/day,etc.). In some embodiments, a single reduced dose (e.g., 15 mg, 14 mg,13 mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2mg, 1 mg) is given each day.

In some embodiments, the present invention provides formulations ofFocalin (e.g., nanoparticulate formulations, non-nanoparticulateformulations, combinations thereor) at doses of less than 20 mg/day(e.g., <10 mg/day, <5 mg/day, <2 mg/day, <1 mg/day, etc.). In someembodiments, a single dose of Focalin is given each day (e.g., <20 mg,<15 mg, <10 mg, <5 mg, <4 mg, <3 mg, <2 mg, <1 mg). In some embodiments,multiple doses (e.g., 2, 3, 4, 5, 6, or more) of Focalin are given eachday. In some embodiments, individual does contain 10 or less mg/dose ofFocalin (e.g., 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1mg, 0.5 mg, 0.25 mg, 0.1 mg). In some embodiments, standard benefit(e.g., reduced ADHD symptoms) is achieved with a reduced dose ofFocalin. In some embodiments, a single reduced dose of Focalin is giveneach day.

B. Non-Stimulant

In some embodiments, non-stimulant pharmaceuticals for use with thepresent invention include Atomoxetine (e.g. Strattera, etc.), Guanfacine(e.g. Intuniv, etc.), Clonidine, etc. Those of skill in the willrecognize that this list is not limiting and recognize additionalnon-stimulant pharmaceuticals which will find use with embodiments ofthe present invention.

In certain embodiments, non-stimulant pharmaceuticals are formulatedaccording to any embodiments described herein, for example:nanoparticulate formulation, non-nanoparticulate formulation, combinednanoparticulate/non-nanoparticulate formulation, immediate release,delayed release, sustained release, co-administration (e.g., with one ormore stimulants, with one or more additional non-stimulants), anysuitable combinations thereof, etc.

In some embodiments, the non-stimulant guanfacine (or anothernon-stimulant is administered to subjects (e.g., subjects suffering fromADHD). In some embodiments, guanfacine is administered in any suitableformulation (e.g., delayed release, immediate release, enteric coating,nanoparticulate, non-nanoparticulate, combinations thereof, etc.). Insome embodiments, one or more doses of guanfacine are administered eachday (e.g., 2, 3, 4, 5, 6, or more). In some embodiments, individual doescontain 4 mg/dose or less of guanfacine (e.g., 4 mg, 3.5 mg, 3 mg, 2.5mg, 2 mg, 1.5 mg, 1 mg, 0.75 mg, 0.5 mg, 0.25 mg, 0.1 mg, and dosestherein). In some embodiments, 4 mg or less of guanfacine isadministered per day (e.g., 4 mg, 3.5 mg, 3 mg, 2.5 mg, 2 mg, 1.5 mg, 1mg, 0.75 mg, 0.5 mg, 0.25 mg, 0.1 mg, and amounts therein). In someembodiments, standard benefit (e.g., reduced ADHD symptoms) is achievedwith a reduced dose of guanfacine. In some embodiments, a single reduceddose of guanfacine is given each day. In some embodiments, multipleformulations (e.g., release profiles,nanoparticulate/non-nanoparticulate, etc.) of guanfacine are provided ina single pharmaceutical composition. In some embodiments, similarlyreduced dosages are provided of other non-stimulant pharmaceuticals(e.g., in addition to guanfacine or instead of guanfacine) in anysuitable formulations.

C. Nanoparticulate Formulation

In some embodiments, the present invention provides nanoparticulateformulations of one or more pharmacologic agents. In some embodiments, asingle pharmacologic agent is provided in a nanoparticulate formulation.In some embodiments, the present invention provides nanoparticulateformulations comprising one or more pharmacologic agents (e.g., astimulant (e.g., Adderall, Focalin, etc.)) for the treatment of ADHD. Insome embodiments, the present invention provides nanoparticulateformulations comprising one or more stimulant pharmacologic agents. Insome embodiments, the present invention provides nanoparticulateformulations comprising one or more non-stimulant pharmacologic agents.In some embodiments, the present invention provides nanoparticulateformulations comprising one or more stimulant pharmacologic agents andone or more non-stimulant pharmacologic agents. In some embodiments,methods of making nanoparticulate formulations comprising pharmacologicagents, and uses and methods of administration thereof are understood inthe art (See, e.g., U.S. Pat. No. 5,145,648; U.S. Pat. No. 5,641,515;U.S. Pat. No. 6,592,903; U.S. Pat. No. 5,585,108; U.S. Pat. No.5,518,738; U.S. Pat. No. 6,375,986; U.S. Pat. No. 7,198,795; U.S. Pat.No. 5,518,187; U.S. Pat. No. 5,862,999; U.S. Pat. No. 5,718,388; U.S.Pat. No. 5,510,118; herein incorporated by reference in theirentireties). In some embodiments, nanoparticulate formulation providespharmaceutical compositions with enhanced bioavailability. In someembodiments, nanoparticulate formulation provides pharmaceuticalcompositions with desirable release characteristics (e.g. controlledrelease, delayed release, slow release, etc.). In some embodiments,nanoparticulate formulation provides pharmaceutical compositions withrapid bioavailability (e.g., <1 hour, <30 minutes, <15 minutes, <5minutes, <1 minute, <30 seconds, <10 seconds, etc.). In someembodiments, nanoparticulate formulation provides pharmaceuticalcompositions with rapid blood clearance, for example, the majority ofthe pharmaceutical composition is cleared from the blood within 1 hour(e.g., <1 hour, <30 minutes, <15 minutes, <5 minutes, <1 minute, <30seconds, <10 seconds, etc.). In some embodiments, nanoparticulateformulation of pharmacologic agents provides enhanced therapeuticbenefit. In some embodiments, reduced dosage of a nanoparticulateformulation of one or more pharmacologic agents provides similartherapeutic benefit to conventional formulations at conventionaldosages. In some embodiments, nanoparticulate formulation of one or morepharmacologic agents provides reduced side effects (e.g., insomnia,appetite loss, abdominal pain, etc.). In some embodiments,nanoparticulate formulation of one or more pharmacologic agents providesreduced side effects (e.g. insomnia, appetite loss, abdominal pain,etc.) because lower doses are used to achieve the same benefit asconventional formulations. In some embodiments, nanoparticulateformulation of one or more pharmacologic agents provides reduced sideeffects (e.g. insomnia, appetite loss, abdominal pain, etc.) because ofthe rapidity of bioavailability compared to conventional formulations.In some embodiments, nanoparticulate formulation of one or morepharmacologic agents provides reduced side effects (e.g. insomnia,appetite loss, abdominal pain, etc.) because of the rapidity of bloodclearance compared to conventional formulations. In some embodiments,nanoparticulate formulation of one or more pharmacologic agents providesreduced side effects (e.g. insomnia, appetite loss, abdominal pain,etc.) because the controlled release properties of nanoparticulateformulation provide more optimal levels of pharmacologic agentscirculating in the bloodstream of a subject, although the presentinvention is not limited to any particular mechanism of action and anunderstanding of the mechanism of action is not necessary to practicethe present invention. In some embodiments, nanoparticulate formulationof stimulant and/or non-stimulant allows for reduction in dose orstimulant and/or non-stimulant by as much as 75% (e.g. >10%, >25%, >50%,etc.) when compared to conventional treatment. In some embodiments,nanoparticulate formulation of stimulant and/or non-stimulant allowsallows for reduction in stimulant dose by 10-50% (e.g. 10%, 20%, 30%,40%, 50%) when compared to conventional treatment.

In some embodiments, pharmaceutical nanoparticulates (e.g., containingAdderall, containing Focalin, etc.) have a diameter (e.g., meandiameter) of less than about 10 μm (e.g., <10 μm, <5 μm, <2 μm, <1 μm,<500 nm, <200 nm, <100 nm, <50 nm, <20 nm, <10 nm, etc.). In someembodiments, pharmaceutical nanoparticulates (e.g., containing Adderall,containing Focalin, etc.) have a diameter (e.g., mean diameter) of about450-550 nm (e.g., about 500 nm). In some embodiments, pharmaceuticalnanoparticulates (e.g., containing Adderall, containing Focalin, etc.)have a diameter (e.g., mean diameter) of about 350-450 nm (e.g., about400 nm). In some embodiments, pharmaceutical nanoparticulates (e.g.,containing Adderall, containing Focalin, etc.) have a diameter (e.g.,mean diameter) of about 250-350 nm (e.g., about 300 nm). In someembodiments, pharmaceutical nanoparticulates (e.g., containing Adderall,containing Focalin, etc.) have a diameter (e.g., mean diameter) of about150-250 nm (e.g., about 200 nm). In some embodiments, pharmaceuticalnanoparticulates (e.g., containing Adderall, containing Focalin, etc.)have a diameter (e.g., mean diameter) of about 50-150 nm (e.g., about100 nm). In some embodiments, pharmaceutical nanoparticulates (e.g.,containing Adderall, containing Focalin, etc.) have a diameter (e.g.,mean diameter) of about 25-75 nm (e.g., about 50 nm).

In some embodiments, the present invention provides administration ofone or more pharmaceutical agents (e.g., stimulant (e.g., Adderall,Focalin, etc.)) in a nanoparticulate formulation. In some embodiments,formulation of the one or more pharmaceutical agents (e.g., stimulant(e.g., Adderall, Focalin, etc.)) in a nanoparticulate provides one ormore advantages over non-nanoparticulate formulation (e.g., rapidrelease, rapid blood clearance, reduced side-effects, lower dosage,enhanced bioavailability, etc.). In some embodiments, all the activeagents in a pharmaceutical composition are provided in nanoparticulateformulation. In some embodiments, administration as a nanoparticulateallows a similar benefit (e.g. duration of treatment, effectiveness ofsymptom reduction, etc.) as conventional formulations with reduced doseof the therapeutic agent (e.g., stimulant (e.g., Adderall, Focalin,etc.)). In some embodiments, reducing the dose of the therapeutic agent(e.g., stimulant (e.g., Adderall)) reduces negative side effects (e.g.insomnia, loss of appetite, abdominal pain, etc.) associated therewith(e.g. associated with large doses (e.g. large doses required forprolonging duration of therapeutic benefit). In some embodiments, rapidrelease of the therapeutic agent (e.g., stimulant (e.g., Adderall,Focalin, etc.)) reduces the associated side effects and/or the requireddose. In some embodiments, rapid blood clearance of the therapeuticagent (e.g., stimulant (e.g., Adderall, Focalin, etc.)) reduces theassociated side effects.

In some embodiments, one or more pharmaceutical agents are provided inboth a nanoparticulate formulation and non-nanoparticulate formulation(e.g., convention formulation, delayed-release formulation, entericallycoated, etc.). In some embodiments, providing one or more agents in twodifferent formulations (e.g., nanoparticulate and non-nanoparticulate)provides enhanced bioavailability, reduced side effects, prolongedeffect, reduced dosage, etc. In some embodiments, a singlepharmaceutical agent (e.g., a stimulant (e.g., Adderall, Focalin, etc.))is provided in both a nanoparticulate formulation andnon-nanoparticulate formulation (e.g., convention formulation,delayed-release formulation, enterically coated, etc.). In someembodiments, providing a pharmaceutical agent in two differentformulations (e.g., nanoparticulate and non-nanoparticulate) providesenhanced bioavailability, reduced side effects, prolonged effect,reduced dosage, etc.

In some embodiments, nanoparticulate formulation of a therapeutic agent(e.g., stimulant (e.g., Adderall, Focalin), non-stimulant, etc.) allowsfor reduction in stimulant dose by as much as 75%(e.g. >10%, >25%, >50%, etc.) when compared to conventional modes ofadministration. In some embodiments, nanoparticulate formulation allowsfor reduced dosage (e.g., 9 mg/dose, 8 mg/dose, 7 mg/dose, 6 mg/dose, 5mg/dose, 4 mg/dose, 3 mg/dose, 2 mg/dose, 1 mg/dose, or less). In someembodiments, nanoparticulate formulation of a therapeutic agent (e.g.,stimulant (e.g., Adderall, Focalin, etc.), non-stimulant, etc.) providesenhanced bioavailability by as much as 100-fold (e.g. >1.1-fold . . .1.2-fold . . . 1.5-fold . . . 2-fold . . . 5-fold . . . 10-fold . . .20-fold . . . 50-fold . . . 100-fold, etc.) when compared toconventional modes of administration. In some embodiments,nanoparticulate formulation speeds the rate at which a pharmaceuticalagent (e.g., a stimulant (e.g., Adderall, Focalin, etc.), non-stimulant,etc.) becomes bioavailable by as much as 100-fold (e.g. >1.1-fold . . .1.2-fold . . . 1.5-fold . . . 2-fold . . . 5-fold . . . 10-fold . . .20-fold . . . 50-fold . . . 100-fold, etc.) when compared toconventional modes of administration. In some embodiments,nanoparticulate formulation speeds the rate at which a pharmaceuticalagent (e.g., a stimulant (e.g., Adderall, Focalin, etc.), non-stimulant,etc.) is cleared from the blood by as much as 100-fold (e.g. >1.1-fold .. . 1.2-fold . . . 1.5-fold . . . 2-fold . . . 5-fold . . . 10-fold . .. 20-fold . . . 50-fold . . . 100-fold, etc.) when compared toconventional modes of administration.

In some embodiments, the present invention provides a low dose and rapidonset (e.g., ultrafast) nanoparticulate formulation of stimulant (e.g.,amphetamine or methylphenidate). In some embodiments, the presentinvention provides a low dose (e.g., 10% . . . 20% . . . 30%, etc. lowerdose of stimulant with same efficacy as approved stimulant dose) andultrafast onset (e.g., on set of action within: 5 minutes . . . 10minutes . . . 15 minutes . . . 20 minutes . . . 30 minutes . . . 45minutes . . . 60 minutes, etc. of administration) nanoparticulateformulation of stimulant (e.g., amphetamine or methylphenidate). In someembodiments, a nanoparticulate formulation of stimulant (e.g.,amphetamine or methylphenidate) allows for reduction in dose compared tonon-nanoparticulate formulation (e.g., by 10-50%, by 20%, etc.) with thesame efficacy. In some embodiments, a nanoparticulate formulation ofstimulant (e.g., amphetamine, methylphenidate, dexmethylphenidate)allows for reduction in dose compared to non-nanoparticulate formulationby 1 mg or more (e.g., 1 mg . . . 2 mg . . . 3 mg . . . 4 mg . . . 5 mg. . . 6 mg . . . 7 mg . . . 8 mg . . . 9 mg, or more) with the sameefficacy. In some embodiments, a nanoparticulate formulation ofstimulant (e.g., amphetamine or methylphenidate) allows for ultrafastonset of action within 30 minutes of administration (e.g., <30 minutes,<20 minutes, <10 minutes, <5 minutes, etc.). In some embodiments,nanoparticulate formulated stimulant (e.g., amphetamine ormethylphenidate) is provided as an orally disintegrating tablet (e.g., atablet that need not be actively swallowed) to further enhance speedstimulant delivery. In some embodiments, low dose, ultrafast onset,nanoparticulate formulation stimulant (e.g., amphetamine ormethylphenidate) is administered as needed (e.g., PRN basis) to assistin managing ADHD.

D. Co-Administration

In some embodiments, the present invention provides a combinationtherapy.

In some embodiments, two or more pharmaceutical agents (e.g., stimulantand non-stimulant) are co-administered. In some embodiments, twosynergistic pharmacological agents (e.g., stimulant and non-stimulant)are co-administered (e.g., concurrent administration/sequential release)to provide prolonged benefit to the patient while reducing side effectsassociated with one or either individual agent. In some embodiments,co-administration (e.g., concurrent administration/sequential release)allows reduced dose of one or both agents relative to the amount thatwould be administered as a single agent therapy. In some embodiments,one or both agents are formulated (e.g. nanoparticle formulation) toprovide an additional basis for lowered dosage. In some embodiments,reduced dose of one or both co-administered agents provides a reductionin associated side effects (e.g. insomnia, loss of appetite, abdominalpain, etc.).

In some embodiments, formulations of stimulant and non-stimulantpharmaceuticals are provided to maintain the efficacy of individual drugtreatments at reduced dose regimens. In some embodiments, one agent isadministered as a nanoparticulate to provide rapid bioavailabilityand/or rapid clearance of the agent.

In some embodiments a first pharmacologic agent and a secondpharmacologic agent provide treatment of the same disorder, disease,condition, and/or symptoms thereof. In some embodiments, first andsecond agents treat the same disorder, disease, condition, and/orsymptoms thereof through different pharmacologic mechanisms. In someembodiments, the differing mechanisms allow for prolonged reduction insymptoms over administration of a single agent. In some embodiments, thediffering mechanisms allow for reducing the total dose of one or bothpharmacological agents. In some embodiments, the differing mechanismshelp reduce side effects associated with one or both agents (e.g.insomnia, abdominal pain, and/or loss of appetite). In some embodiments,reduction in dose of one or both pharmacological agents helps reduceside effects associated with one or both agents.

In some embodiments, stimulant (e.g., nanoparticulate formulated) andnon-stimulant are co-administered in pharmaceutical compositions (e.g.,to provide treatment of symptoms at reduced dosage). In someembodiments, the combination of stimulant and non-stimulant therapeuticsprovides the same efficacy as the therapeutics on their own, only atlower dose. In some embodiments, the release of the non-stimulant andstimulant is controlled to maintain efficacy of stimulant-only treatmentat reduced dose. In some embodiments, any dose combination of stimulantand non-stimulant that provides the same (or better) efficacy ofstimulant-only treatment at reduced dose is within the scope of thepresent invention. For example, in some embodiments, a pharmaceuticalcomposition comprises 10 mg amphetamine (rapid release) and 4 mg ofguanfacine (delayed release). In some embodiments, a pharmaceuticalcomposition comprises 9 mg of nanoparticulate amphetamine (rapidrelease) and 4 mg of guanfacine (delayed release). These are onlyexample of suitable dose combinations. Any combinations doses andrelease schedule that provides similar efficacy to standard treatmentsat reduced dose is within the scope of the present invention.

In some embodiments, the methods comprising administering to a subjectsuffering from ADHD a combination therapeutic agent comprising astimulant pharmacologic agent and a non-stimulant pharmacologic agent,wherein the stimulant pharmacologic agent and the non-stimulantpharmacologic agent are formulated for release according to separateschedules, and wherein administration of the combination therapeuticagent. Such embodiments provide effective relief of symptoms of ADHDwhile minimizing or avoiding undesired side-effects. In someembodiments, the combination therapeutic agent provides effective reliefof symptoms of ADHD using lower doses of the stimulant pharmacologicagent and/or the non-stimulant pharmacologic agent than when thestimulant pharmacologic agent or the non-stimulant pharmacologic agentare used alone to treat ADHD (i.e., the dose administered is lower thanthe normal recommended dose for a particular subject, taking intoaccount age, size, gender, or other factors). In some embodiments, thecombination therapeutic agent provides effective relief of symptoms ofADHD with fewer or reduced side effects from the stimulant pharmacologicagent and/or the non-stimulant pharmacologic agent than when thestimulant pharmacologic agent or the non-stimulant pharmacologic agentare used alone to treat ADHD. In some embodiments, the combinationtherapeutic agent provides effective relief of symptoms of ADHD forlonger duration than when the stimulant pharmacologic agent or thenon-stimulant pharmacologic agent are used alone to treat ADHD. In someembodiments, the stimulant pharmacologic agent is formulated to beginrelease upon administration to a subject. In some embodiments, thestimulant pharmacologic agent is formulated to release over the courseof 0.5 to 6 hours, although other ranges may be used, as desired. Insome embodiments, the non-stimulant pharmacologic agent is formulated torelease over the course of 3 to 12 hours, although other ranges may beused, as desired. In some embodiments, the non-stimulant pharmacologicagent is formulated to begin release upon administration to a subject.In some embodiments, the non-stimulant pharmacologic agent is formulatedfor delayed release. In some embodiments, the delayed release comprisesrelease beginning 3 to 6 hours after administration to a subject,although other ranges may be used, as desired. In some embodiments, thesubject is a child (e.g., a human child under the age of 18, 16, 14, 12,10, 8, 6, etc.). In some embodiments, the combination therapeutic agentprovides effective relief of symptoms of ADHD for 8 to 16 hours. Sideeffects, such as problems with sleep or appetite are reduced oreliminated in the later hours of the day upon a morning administrationof the agents.

In some embodiments, the present invention provides a method oftreating, preventing, or ameliorating signs or symptoms of a disease orcondition in a subject by administering a pharmaceutical composition tothe subject. In some embodiments, the pharmaceutical agent comprises afirst formulation and a second formulation. In some embodiments, thefirst formulation comprises a nanoparticulate of one or morepharmaceutical agents. In some embodiments, the first formulationcomprises one or more pharmaceutical agents and one or morenon-pharmaceutical compositions. In some embodiments, the firstformulation is configured for rapid-release of one or morepharmaceutical agents upon administration to a subject. In someembodiments, the second formulation comprises one or more pharmaceuticalagents. In some embodiments, the second formulation comprises one ormore pharmaceutical agents and one or more non-pharmaceuticalcompositions. In some embodiments, the second formulation is configuredfor slow-release of one or more pharmaceutical agents uponadministration to a subject. In some embodiments, administration of afirst formulation and a second formulation reduces side effects relatedto one or more pharmaceutical agents administered to a subject (e.g.,pharmaceutical agents in the first formulation, pharmaceutical agents inthe second formulation, pharmaceutical agents in both formulations).

In some embodiments, the present invention provides co-administration ofa first stimulant pharmaceutical with a second pharmaceutical (e.g., adifferent formulation of the same pharmaceutical, a different stimulant,a non-stimulant, etc.). In some embodiments, the present inventionprovides co-administration of a first stimulant pharmaceutical with asecond non-stimulant pharmaceutical. In some embodiments, one or both ofthe first stimulant pharmaceutical and second non-stimulantpharmaceutical are nanoparticle formulated. In some embodiments, thepresent invention provides co-administration of a first stimulantpharmaceutical (e.g. norepinephrine reuptake inhibitor (e.g.amphetamines, methylphenidate, dexmethylphenidate, etc.) with a secondnon-stimulant pharmaceutical (e.g. alpha adrenergic agonist (e.g.guanfacine, clonidine, etc.) for the treatment of attention deficithyperactive disorder (ADHD). In some embodiments, a stimulant andnon-stimulant are co-administered to provide an extended duration ofeffective treatment of symptoms without increasing the dose of eitheragent. In some embodiments, a stimulant and non-stimulant areco-administered to provide an extended duration of effective treatmentof symptoms without significant side effects (e.g. insomnia, appetiteloss, abdominal pain). In some embodiments, co-administration of astimulant agent and non-stimulant agent provides extended effectivetreatment of ADHD (e.g. >8 hours, >10 hours, >12 hours, >14 hours, >16hours, up to 24 hours) without side effects associated with large dosesof stimulants. In some embodiments, co-administration of a stimulantagent and non-stimulant agent provides the same duration of symptomrelief as a high dose stimulant-only treatment, using reduced dosage ofstimulant and with reduced stimulant side effects (e.g. reducedinsomnia, reduced appetite loss, reduced abdominal pain, etc.). In someembodiments, co-administration of a stimulant agent and non-stimulantagent provides extended duration of symptom relief over stimulant-onlytreatment (e.g. additional 2 hours of reduced symptoms, additional 4hours of reduced symptoms, additional 6 hours of reduced symptoms,additional 8 hours of reduced symptoms) without additional stimulantside effects (e.g. insomnia, appetite loss, abdominal pain, etc.).

In some embodiments, co-administration of stimulant and non-stimulantusing formulations of the present invention allows for reduction instimulant dose by as much as 75% (e.g. >10%, >25%, >50%, etc.) whencompared to stimulant-only treatment. In some embodiments,co-administration of stimulant and non-stimulant using formulations ofthe present invention allows for reduction in stimulant dose by 10-50%(e.g. 10%, 20%, 30%, 40%, 50%) when compared to stimulant-onlytreatment. In some embodiments, co-administration of stimulant andnon-stimulant using formulations of the present invention allows forreduction in non-stimulant dose by as much as 75%(e.g. >10%, >25%, >50%, etc.) when compared to non-stimulant-onlytreatment. In some embodiments, co-administration of stimulant andnon-stimulant using formulations of the present invention allows forreduction in non-stimulant dose by 10-50% (e.g. 10%, 20%, 30%, 40%, 50%)when compared to non-stimulant-only treatment.

E. Release Profile

In some embodiments, pharmaceutical agents of the present invention areformulated for slow release, delayed release, immediate release, timedrelease, or combinations thereof. In some embodiments, a pharmaceuticalagent, or portions of a pharmaceutical agent, is enterically coated toprotect the agent or agents from dissolving in the stomach. In someembodiments, enterically coated pharmaceuticals dissolve, releasingpharmaceutical agents, upon reaching a desired location (e.g., the smallintestine). In some embodiments, enteric coating of an agent delaysrelease of the agent for several hours (e.g. 3 hours, 4 hour, 5 hours, 6hours, 7 hours, etc.). In some embodiments, an enterically coated agentmay be formulated for immediate release upon loss of the enteric coatingor for slow release (e.g. over the course of hours). In someembodiments, an enterically coated agent may be formulated for immediaterelease upon loss of the enteric coating.

F. Combination Formulations

The present invention provides therapeutic benefit with reduced sideeffects. In some embodiments, one or more of nanoparticulateformulation, co-administration of stimulant and non-stimulant drugs, andspecific drug-release regimes enable reduced dosages and/or reduced sideeffects with little or no loss of therapeutic benefit. Particularembodiments, of the invention employ one or more of nanoparticulateformulation, co-administration of stimulant and non-stimulant drugs, andspecific drug-release regimes. In certain embodiments, the presentinvention provides any combination of the various embodiments describedherein (e.g., (e.g., release profiles, formulations (e.g.,nanoparticulate, non-nanoparticulate), drug combinations, etc.). Forexample, in particular embodiments, dosing regimens (e.g., releaseprofile, doses, drugs provided) may be provided in eithernanoparticulate or non-nanoparticulate formulation. Additionally, any ofthe various embodiments of the invention described herein (e.g., releaseprofiles, formulations, drug combinations, etc.) may find use in thetreatment of pediatric subjects (e.g., 0-19 years), infant subjects(e.g., 0-2), children (e.g., 2-12 years), adolescent subjects (e.g.,13-19 years), and/or adult subjects (e.g., 20+ years).

In some embodiments, the present invention provides co-administration ofa first agent with a second agent. In some embodiments, one or bothagents are formulated as nanoparticulates. In some embodiments, thepresent invention provides co-administration of a first agent with atime-released second agent. In some embodiments, the first agent is alsotime released. In some embodiments, the first agent (e.g., stimulant(e.g., Adderall, Focalin, etc.)) is timed to release early in thetreatment course (e.g., first agent is in nanoparticulate). In someembodiments, the first agent is formulated (e.g., nanoparticulate) to becleared from the blood early in the treatment course. In someembodiments, a first agent is formulated with one or more additionalpharmaceutical and/or non-pharmaceutical agents. In some embodiments,the second agent is timed to release late in the treatment course. Insome embodiments, the second agent in timed to release throughout thetreatment course. In some embodiments, administration of the secondagent with the first agent allows a similar benefit (e.g. duration oftreatment, effectiveness of symptom reduction, etc.) from treatment withreduced dose of the first agent. In some embodiments, reducing the doseof the first agent reduces negative side effects (e.g. insomnia, loss ofappetite, abdominal pain, etc.) associated with the first agent (e.g.associated with large doses (e.g. large doses required for prolongingduration of the benefit of the first agent). In some embodiments, rapidrelease of the first agent reduces the associated side effects and/orthe required dose. In some embodiments, rapid blood clearance of thefirst agent reduces the associated side effects. In some embodiments,administration of the second agent with the first agent allows a similarbenefit (e.g. duration of treatment) from treatment with reduced dose ofthe second agent. In some embodiments, reducing the dose of the secondagent reduces negative side effects (e.g. insomnia, loss of appetite,abdominal pain, etc.) associated with the second agent (e.g. associatedwith large doses (e.g. large doses required for prolonging duration ofthe benefit of the second agent). In some embodiments, a lower dose ofthe first agent at an early stage in the treatment course causes thefirst agent to be substantially metabolized during the later portion ofthe treatment course such that its active dosage does not exhibitunwanted side effects. In such embodiments, the second agent is activein the later portion of the treatment course to provide or significantlycontribute to the therapeutic benefit—without the associated negativeeffects of the first agent. In some embodiments, nanoparticulateformulation of one or more agents reduces side effects associated withthose agents (e.g., due to rapid release and/or rapid clearance ofnanoparticulate formulated agents).

In some embodiments, the present invention provides timed releaseco-administration of a first stimulant pharmaceutical (e.g.norepinephrine reuptake inhibitor (e.g. amphetamines (e.g., Adderall),methylphenidate, etc.)) with a second non-stimulant pharmaceutical (e.g.alpha adrenergic agonist (e.g. guanfacine, clonidine, etc.)) for thetreatment of ADHD. In some embodiments, a first stimulant pharmaceuticalis formulated for immediate release, providing a subject with reducedsymptoms beginning early in the treatment time course (e.g. within 10minutes, within 30 minutes, within 1 hour). In some embodiments, a firststimulant pharmaceutical is formulated to last for several hours (e.g. 3hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours). In someembodiments, a first stimulant pharmaceutical is formulated (e.g., in ananoparticulate) for rapid release and/or clearance (e.g., peak bloodconcentration in <15 minutes). In some embodiments, a secondnon-stimulant pharmaceutical is formulated for delayed release,providing a subject with reduced symptoms beginning midway through thetreatment time course (e.g. beginning at approximately 3 hours, 4 hours,5 hours, 6 hours, 7 hours) and lasting for several hours (e.g. 3 hours,4 hours, 5 hours, 6 hours, 7 hours, 8 hours). In some embodiments, asecond non-stimulant pharmaceutical is formulated for slow release,providing a subject with reduced symptoms (e.g. mild reduction insymptoms) beginning early in the treatment time course (e.g. within 10minutes, within 30 minutes, within 1 hour) and providing a low dosagereleased over multiple hours (e.g. 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, etc.). In someembodiments, slow-release or delayed-release of the second non-stimulantpharmaceutical agent extends the effective reduction of ADHD symptoms ofthe first stimulant pharmaceutical agent, without an increase in dose ofthe stimulant. In some embodiments, slow-release or delayed-release ofthe second non-stimulant pharmaceutical agent extends the effectivereduction of ADHD symptoms of the first stimulant pharmaceutical agent,using a lower dose of the stimulant. In some embodiments, slow-releaseor delayed-release of the second non-stimulant pharmaceutical agentextends the effective reduction of ADHD symptoms of the first stimulantpharmaceutical agent, without stimulant-related side effects (e.g.without significant stimulant-related side effects.

In some embodiments, pharmaceutical compositions provided hereincomprise drug-release profiles that achieve release of one or morepharmaceuticals in 1 or more release peaks (e.g., 1, 2, 3, 4, 5, 6, ormore). In certain embodiments, separate drugs (e.g., stimulant andnon-stimulant) within a pharmaceutical formulation produce separaterelease peaks. In some embodiments, separate drugs (e.g., stimulant andnon-stimulant) within a pharmaceutical formulation are released during asingle release peak (e.g. immediate release). In some embodiments, asingle drug drugs (e.g., stimulant and non-stimulant) within apharmaceutical formulation is released in two or more separate releasepeaks (e.g., 2, 3, 4, 5, 6, or more). In some embodiments, apharmaceutical composition is provided that produces 3 release peaks(e.g., 2 stimulant release peaks and 1 non-stimulant release peak). Insome embodiments, a pharmaceutical composition is configured formulti-peak release of a single pharmaceutical agent (e.g., stimulant(e.g. Adderall, Focalin, etc.) and/or non-stimulant). In someembodiments, a pharmaceutical composition is configured for multi-peakrelease of a multiple pharmaceutical agents (e.g., stimulants (e.g.Adderall, Focalin, etc.) and/or non-stimulants).

In some embodiments, the present invention provides a controlledsequential release formulation of stimulant (e.g., amphetamine ormethylphenidate) followed by non-stimulant (e.g., guanfacine) for oncedaily administration. In some embodiments, one or both of the stimulant(e.g., amphetamine or methylphenidate) and non-stimulant therapeutic(e.g., guanfacine) are formulated as a nanoparticulate. In someembodiments, a sequential-release formulation comprises nanoparticulateformulated stimulant (e.g., amphetamine or methylphenidate) andnon-nanoparticulate formulated non-stimulant therapeutic (e.g.,guanfacine). In some embodiments, the non-stimulant therapeutic (e.g.,guanfacine) in a controlled sequential release formulation is formulatedfor delayed release following initial administration (e.g., 1 hour delay. . . 2 hour delay . . . 3 hour delay . . . 4 hour delay . . . 5 hourdelay . . . 6 hour delay, etc.). In some embodiments, controlledsequential release formulation provides ultrafast onset of action ofnanoparticulate formulated stimulant (e.g., amphetamine ormethylphenidate) following administration (e.g., <45 minutes, <30minutes, <20 minutes, <10 minutes, <5 minutes, etc.). In someembodiments, controlled sequential release formulation maintainsstimulant (e.g., amphetamine or methylphenidate) levels for 4 or morehours (e.g., 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours,etc.). In some embodiments, controlled sequential release formulationmaintains therapeutic levels of non-stimulant therapeutic (e.g.,guanfacine) for over 4 hours following onset of action (e.g., 5 hours, 6hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13hours, 14 hours, 15 hours, 16 hours, etc.). In some embodiments,controlled sequential release formulation allows for reduction in dose(e.g., 20%, 30%, 40%, 50%, 60%, 70%) of stimulant (e.g., amphetamine ormethylphenidate), non-stimulant (e.g., guanfacine), or both overstandard formulations. In some embodiments, lower daily dose ofstimulant (e.g., amphetamine or methylphenidate) reducesstimulant-associated side effects (e.g., insomnia, appetite suppression,etc.). In some embodiments, reduction in stimulant (e.g., amphetamine ormethylphenidate) levels 8 hours after administration reducesstimulant-associated side effects (e.g., insomnia, appetite suppression,etc.). In some embodiments, the offsetting action of non-stimulanttherapeutic action reduces stimulant-associated side effects (e.g.,insomnia, appetite suppression, etc.). In some embodiments, thecombination of: lower daily dose of stimulant, reduction in stimulantlevels 8 hours after administration, and the offsetting action ofnon-stimulant therapeutic reduces stimulant-associated side effects(e.g., insomnia, appetite suppression, etc.). In some embodiments,once-daily administration of controlled sequential release formulationof stimulant (e.g., amphetamine or methylphenidate) followed bynon-stimulant (e.g., guanfacine) reduces potential for abuse because ofreduced amount of stimulant in each dose and offsetting action ofnon-stimulant if crushed and extracted. In some embodiments,nanoparticulate formulated stimulant (e.g., amphetamine ormethylphenidate) is provided as an orally disintegrating tablet.

In some embodiments, co-administration of stimulant (e.g., amphetamineor methylphenidate) and non-stimulant in a controlled sequential releaseformulation (e.g., stimulant onset of action within 30 minutes andlasting for 8 hours, nonstimulant released at 4 hours and maintaininglevels for 7-14 hours) provides a reduction in the daily dose of each ofthe individual components by 25-75% (e.g., about 30%, about 40%, about50%, about 60%, about 70%). In some embodiments, nanoparticulateformulation of stimulant provides ultrafast onset of action and furtherreduction in dose by 10-50% (e.g., about 20%, about 30%, about 40%). Insome embodiments, lower daily dose of stimulant and earlier decline inPK (e.g., before evening meal and/or bedtime) reduces stimulant-relatedside effects (e.g., insomnia, appetite suppression, etc.). In someembodiments, ultrafast onset of stimulant action provides control ofsymptoms quickly upon administration. In some embodiments, non-stimulantoffsets remaining stimulant effect near the end of the day.

G. Pediatric

In some embodiments, the present invention provides combination therapyfor the treatment of pediatric ADHD. In some embodiments, the subjectbeing treated is an infant (e.g., <2 years), child (e.g., 2-12 years),or adolescent (e.g., 13-19 years). In some embodiments, the presentinvention provides timed release co-administration of a first stimulantpharmaceutical (e.g. norepinephrine reuptake inhibitor (e.g.amphetamines, methylphenidate, dexmethylphenidat etc.)) with a secondnon-stimulant pharmaceutical (e.g. alpha adrenergic agonist (e.g.guanfacine, clonidine, etc.)) for the treatment of pediatric ADHD (e.g.patients under 25, under 22, under 18, under 16, etc.). In someembodiments, pediatric patients present difficulties in compliance withscheduled administration of pharmaceutical treatment. In someembodiments, the school day and/or other childhood-related factors (e.g.desire not to take medicine, desire not to take medicine in front offriends, difficulty remembering to take medicine, etc.) makesadministration of a single pharmaceutical dose in the morning thepreferred method of treatment for increasing therapy compliance. In someembodiments, traditional stimulant therapies require a large dose ofstimulant (e.g. >10 mg, >20 mg, >50 mg, etc.) to provide benefit (e.g.reduced ADHD symptoms, including, but not limited to, ease ofdistraction, loss of attention to details, forgetfulness, loss of focus,boredom, learning disabilities, difficulty completing projects, problemswith listening, daydreaming, confusion, slow movement, difficultiesprocessing information, difficulties following instructions, fidgeting,excessive talking, restlessness, excessive motion, impatience, andoutbursts) throughout the desired course (e.g. the entire school day,school day plus afterschool activities, >8 hours, >10 hours, >12 hours,etc.). Large doses of stimulant used in traditional stimulant regimesresult in significant side effects such as insomnia, abdominal pain, andloss of appetite that carry over into the later part of the day wherethey become life disruptive for the subject and those around thesubject.

Insomnia, abdominal pain, and loss of appetite have significant impacton a child's health and quality of life. In some embodiments, thepresent invention provides time-released co-administration of astimulant and non-stimulant in a single dose (e.g. a single dose takenat the beginning of the day or before school). In some embodiments, thepresent invention provides timed release co-administration of a firststimulant pharmaceutical (e.g. norepinephrine reuptake inhibitor (e.g.amphetamines (e.g., Adderall), methylphenidate, Focalin, etc.)) with asecond non-stimulant pharmaceutical (e.g. alpha adrenergic agonist (e.g.guanfacine, clonidine, etc.)) for full-day treatment of pediatric ADHD(e.g. the entire school day, school day plus afterschool activities, >8hours, >10 hours, >12 hours, etc.). In some embodiments,co-administration of stimulant and non-stimulant provides extendedreduction of symptoms ADHD (e.g. the entire school day, school day plusafterschool activities, >8 hours, >10 hours, >12 hours, etc.) withoutdetrimental side effects (e.g. insomnia, appetite loss, abdominal pain,etc.). In some embodiments, co-administration of stimulant andnon-stimulant provides extended reduction of ADHD symptoms withoutsignificant detrimental side effects (e.g. insomnia, appetite loss,abdominal pain, etc.). In some embodiments, co-administration ofstimulant and non-stimulant provides extended reduction of ADHD symptomswith significantly reduced detrimental side effects (e.g. insomnia,appetite loss, abdominal pain, etc.).

In some embodiments, various embodiments described herein also find usein treatment of adults with ADHD or other conditions. Unlessspecifically noted otherwise, the compositions and methods describedherein are not limited to a particular population.

H. Additional Formulations

In some embodiments, pharmaceutical agents of the present inventioncontain additional agents to control side effects (e.g. insomnia,appetite loss, abdominal pain, etc.). In some embodiments, peppermintoil is included with a pharmaceutical agent to reduce abdominal painassociated with one or more pharmaceutical agents (e.g. stimulant agent,non-stimulant agent, etc.). In some embodiments, peppermint oil isincluded with a pharmaceutical agent to reduce abdominal pain associatedwith high doses of one or more pharmaceutical agents.

In some embodiments, pharmaceutical compositions and formulations areprovided that lack undesirable salts of other additives (e.g.,aspartame, saccharine, etc.). In some embodiments, pharmaceuticalcompositions and formulations are provided with 4 or fewerpharmaceutically acceptable salts (e.g., 4, 3, 2, 1, 0).

When used for the above purposes, said pharmaceutical compound may beadministered via any desired oral, parenateral, topical, intervenous,transmucosal, and/or inhalation routes. The pharmaceutical compound maybe administered in the form of a composition which is formulated with apharmaceutically acceptable carrier and optional excipients, flavors,adjuvants, etc. in accordance with good pharmaceutical practice.

The present invention also provides pharmaceutical compositions in aunit dosage form for administration to a subject, comprisingpharmaceutical compounds (e.g. stimulant and non-stimulant) and one ormore nontoxic pharmaceutically acceptable carriers, adjuvants orvehicles. The amount of the active ingredients (e.g. stimulant andnon-stimulant) that may be combined with such materials to produce asingle dosage form will vary depending upon various factors, asindicated above. A variety of materials can be used as carriers,adjuvants, and vehicles in the composition of the invention, asavailable in the pharmaceutical art.

In some embodiments of the present invention, compositions areadministered to a patient alone or in combination with other therapies,pharmaceuticals, supplements, and/or a specified diet, or inpharmaceutical compositions where it is mixed with excipient(s) or otherpharmaceutically acceptable carriers. In one embodiment of the presentinvention, the pharmaceutically acceptable carrier is pharmaceuticallyinert. In another embodiment of the present invention, compositions(e.g. co-administrations of stimulant and non-stimulant) may beadministered alone to individuals suffering from ADHD.

Depending on the goal of administration (e.g. severity of condition,duration of treatment, etc.), compositions (e.g. co-administrations ofstimulant and non-stimulant) may be formulated and administeredsystemically or locally. Techniques for formulation and administrationmay be found in the latest edition of “Remington's PharmaceuticalSciences” (Mack Publishing Co, Easton Pa.). Suitable routes may, forexample, include oral or transmucosal administration; as well asparenteral delivery, including intramuscular, subcutaneous,intramedullary, intrathecal, intraventricular, intravenous,intraperitoneal, or intranasal administration.

In some embodiments, compositions (e.g. nanoparticulate drugformulations, co-administrations of stimulant and non-stimulant, etc.)are in the form of a solid, semi-solid or liquid dosage form: such astablet, capsule, orally-disintegrating tablets, pill, powder,suppository, solution, elixir, syrup, suspension, cream, lozenge, pasteand spray containing the first and second agents formulatedappropriately to provide the desired time-release profile. As thoseskilled in the art would recognize, depending on the chosen route ofadministration, the composition form is selected. In some embodiments,the pharmaceutical composition (e.g., nanoparticulate, multipleco-administered compounds, etc.) are administered in single or multipledoses. In preferred embodiments, the pharmaceutical compound isadministered in a single dose. In some embodiments, a single oral pillor capsule is provided containing the first and second agents. In somepreferred embodiments, a capsule is used containing the first agent in aform that permits early release and the second agent in a form thatpermits later release. The particular route of administration and thedosage regimen will be determined by one of skill, in keeping with thecondition of the individual to be treated and said individual's responseto the treatment. In some embodiments, a single oral pill or capsule isprovided containing a nanoparticulate formulation of one or moretherapeutic agents (e.g., a stimulant (e.g., Adderall, Focalin, etc.).

In some embodiments, substituents of a composition of the presentinvention may be adjusted to provide desirable solubility or othercharacteristics for administration by any suitable technique.

In some embodiments, the present invention provides nanoparticulateformulations of pharmaceutical agents (e.g., a stimulant (e.g.,Adderall, Focalin, etc.)) for treatment of ADHD. Some embodiments of thepresent invention (e.g., co-administration, nanoparticulate formulation,etc.) provide enhanced benefit at a standard does, reduced side effectsat a standard does (e.g., 10 mg Adderall, 1 mg guanfacine, etc.),standard benefit at a reduced does (e.g., with reduced side effects dueto reduced dose), enhanced benefit at a reduced does (e.g., with reducedside effects due to reduced dose), etc.

EXPERIMENTAL Example 1 ADHD Co-Administration Regimen

Patient dosing is determined on an individual patient basis taking intoaccount the age, size, and weight of the patient; severity of thecondition; and empirical response to the treatment. Exemplary stimulantand non-stimulant dose and time-release regimens within the scope of thepresent invention are provided below. The doses in the followingregimens are determined to be subtherapeutic based on a once-daily 20 mgtherapeutic dose of Adderall XR. One of skill in the art wouldunderstand that the co-administration therapy can be altered, forgeneral practice or for specific patients, in terms of dose, timing ofrelease, and rate of release for either agent. The following doseregimens are contemplated to produce therapeutic effect with reducedside effects.

Exemplary Regimen A.

Patient is administered 10 mg of amphetamine salts (e.g. Dexamphetamine)and 1 mg guanfacine in a single dose in the early part of the day (e.g.morning). The amphetamine salts are formulated for immediate release,and the guanfacine is formulated for delayed release. Although thepresent invention is not limited to any particular mechanism of actionand an understanding of the mechanism of action is not necessary topractice the present invention, it is contemplated that in thisconfiguration the Dexamphetamine provides a rapid reduction in symptomscontinuing through the early hours of the time-course (e.g. morning),and the guanfacine extends the reduction of symptoms throughout thelater portion of the time course (e.g. afternoon); therefore, thecombination reduces symptoms over the entire time-course with reducedside effects caused by multiple doses.

Exemplary Regimen B.

Patient is administered 9 mg of amphetamine salts (e.g. Dexamphetamine)and 0.9 mg guanfacine (10% reduction in total daily dose) in a singledose in the early part of the day (e.g. morning). The amphetamine saltsare formulated for immediate release over approximately 5 hours, and theguanfacine is formulated for release beginning after a 4 hours andcontinuing for approximately 5 hours. Although the present invention isnot limited to any particular mechanism of action and an understandingof the mechanism of action is not necessary to practice the presentinvention, it is contemplated that in this configuration theDexamphetamine provides a rapid reduction in symptoms continuing throughthe early hours of the time-course (e.g. morning), and the guanfacineextends the reduction of symptoms throughout the later portion of thetime course (e.g. afternoon).

Exemplary Regimen C.

Patient is administered 9 mg of amphetamine salts (e.g. Dexamphetamine)and 0.9 mg guanfacine (10% reduction in total daily dose) in a singledose in the early part of the day (e.g. morning). The amphetamine saltsare formulated for release by two separate mechanisms. 5 mg areformulated for immediate release. 4 mg are coated for enteric release(e.g. release after approximately 4 hours). The guanfacine is formulatedfor release beginning after 4 hours and continuing for approximately 5hours. Although the present invention is not limited to any particularmechanism of action and an understanding of the mechanism of action isnot necessary to practice the present invention, it is contemplated thatin this configuration the Dexamphetamine provides a rapid reduction insymptoms continuing through the early hours of the time-course, which issupplemented by the enteric release several hours later. The guanfacineextends the reduction of symptoms throughout the later portion of thetime course (e.g. afternoon) without undesired side effects.

Exemplary Regimen D.

Patient is administered 9 mg of amphetamine salts (e.g. Dexamphetamine)and 0.9 mg guanfacine (10% reduction in total daily dose) in a singledose in the early part of the day (e.g. morning). The amphetamine saltsare formulated for release by two separate mechanisms. 5 mg areformulated for immediate release. 4 mg are coated for enteric release(e.g. release after approximately 4 hours). The guanfacine is coated forenteric release beginning after approximately 4 hours and formulated forslow release continuing over the course of several hours (e.g. 4 hours,5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, etc.). Althoughthe present invention is not limited to any particular mechanism ofaction and an understanding of the mechanism of action is not necessaryto practice the present invention, it is contemplated that in thisconfiguration the Dexamphetamine provides a rapid reduction in symptomscontinuing through the early hours of the time-course, which issupplemented by the enteric release several hours later. The guanfacineextends the reduction of symptoms throughout the late portion of thetime course without undesired side effects.

In any of the above regimens, peppermint oil may be included in theformulation, either as immediate release, or, for example, may beenterically coated (e.g., alone with other components) for immediaterelease after several hours to target both the timing and location ofabdominal pain side effects associated with some therapeutic agents.

In should be noted that the above treatment regimens are not limiting onthe scope of the present invention. These treatment regiments can bealtered to include other pharmaceuticals, other formulations (e.g.,nanoparticulate, non-nanoparticulate, enteric coating, delayed release,immediate release, combinations thereof, etc.), other doses, additionaldoses, etc. It is understood by one in the field that analogous dosingregimens can be provided for other pharmaceuticals, based onconventional therapeutic doses for the pharmaceuticals and using thesame reasoning as is applied in the examples.

Example 2 Nanoparticulate Formulation Dosing

Exemplary stimulant and/or non-stimulant dose and time-release regimens,for use with nanoparticulate formulation, within the scope of thepresent invention is provided below. One of skill in the art wouldunderstand that the regimens can be altered, for general practice or forspecific patients, in terms of dose, formulation, combinations, timingof release, and rate of release for one or more agents.

Exemplary Regimen A.

Patient is administered 10 mg of a nanoparticulate formulation ofamphetamine salts (e.g. Dexamphetamine) in a single dose in the earlypart of the day (e.g. morning). The amphetamine salts are formulated forimmediate release over approximately 5 hours. Although the presentinvention is not limited to any particular mechanism of action and anunderstanding of the mechanism of action is not necessary to practicethe present invention, it is contemplated that in this configuration thenanoparticulate formulation provides enhanced bioavailability ofDexamphetamine, thereby allowing a reduced dose, resulting in reduceside effects.

Exemplary Regimen B.

Patient is administered 6 mg of a nanoparticulate formulation ofamphetamine salts (e.g. Dexamphetamine) and 0.9 mg guanfacine (10%reduction in total daily dose) in a single dose in the early part of theday (e.g. morning). The amphetamine salts are formulated for immediaterelease over approximately 5 hours, and the guanfacine is formulated forrelease beginning after a 4 hours and continuing for approximately 5hours. Although the present invention is not limited to any particularmechanism of action and an understanding of the mechanism of action isnot necessary to practice the present invention, it is contemplated thatin this configuration the nanoparticulate formulation of Dexamphetamineprovides a rapid reduction in symptoms, at a reduced dosage, continuingthrough the early hours of the time-course (e.g. morning), and theguanfacine extends the reduction of symptoms throughout the laterportion of the time course (e.g. afternoon).

Exemplary Regimen C.

Patient is administered 9 mg of a nanoparticulate formulation ofamphetamine salts (e.g. Dexamphetamine) in a single dose in the earlypart of the day (e.g. morning). The nanoparticulate amphetamine saltsare formulated for release by two separate mechanisms. 5 mg areformulated for immediate release. 4 mg are coated for enteric release(e.g. release after approximately 4 hours). The guanfacine is formulatedfor release beginning after 4 hours and continuing for approximately 5hours. Although the present invention is not limited to any particularmechanism of action and an understanding of the mechanism of action isnot necessary to practice the present invention, it is contemplated thatin this configuration the Dexamphetamine provides a rapid reduction insymptoms continuing through the early hours of the time-course, which issupplemented by the enteric release several hours later. It iscontemplated that in this configuration the nanoparticulate formulationprovides enhanced bioavailability of Dexamphetamine, thereby allowing areduced dose, resulting in reduce side effects.

Exemplary Regimen D.

Patient is administered 6 mg of a nanoparticulate formulation ofamphetamine salts amphetamine salts (e.g. Dexamphetamine) and 0.6 mg ananoparticulate formulation of guanfacine in a single dose in the earlypart of the day (e.g. morning). The nanoparticulate amphetamine saltsare formulated for release by two separate mechanisms. 3.5 mg areformulated for immediate release. 2.5 mg are coated for enteric release(e.g. release after approximately 4 hours). The nanoparticulateguanfacine is formulated for release beginning after 4 hours andcontinuing for approximately 5 hours. Although the present invention isnot limited to any particular mechanism of action and an understandingof the mechanism of action is not necessary to practice the presentinvention, it is contemplated that in this configuration theDexamphetamine provides a rapid reduction in symptoms continuing throughthe early hours of the time-course, which is supplemented by the entericrelease several hours later. The guanfacine extends the reduction ofsymptoms throughout the later portion of the time course (e.g.afternoon) without undesired side effects. It is contemplated that inthis configuration the nanoparticulate formulation provides enhancedbioavailability, thereby allowing a reduced dose, resulting in reduceside effects.

Exemplary Regimen E.

Patient is administered 7 mg of a nanoparticulate formulation ofamphetamine salts (e.g. Dexamphetamine) and 0.7 mg of a nanoparticulateformulation of guanfacine (10% reduction in total daily dose) in asingle dose in the early part of the day (e.g. morning). Thenanoparticulate amphetamine salts are formulated for release by twoseparate mechanisms. 4 mg are formulated for immediate release. 3 mg arecoated for enteric release (e.g. release after approximately 4 hours).The guanfacine is coated for enteric release beginning afterapproximately 4 hours and formulated for slow release continuing overthe course of several hours (e.g. 4 hours, 5 hours, 6 hours, 7 hours, 8hours, 9 hours, 10 hours, etc.). Although the present invention is notlimited to any particular mechanism of action and an understanding ofthe mechanism of action is not necessary to practice the presentinvention, it is contemplated that in this configuration theDexamphetamine provides a rapid reduction in symptoms continuing throughthe early hours of the time-course, which is supplemented by the entericrelease several hours later. The guanfacine extends the reduction ofsymptoms throughout the late portion of the time course withoutundesired side effects. It is contemplated that in this configurationthe nanoparticulate formulation provides enhanced bioavailability,thereby allowing a reduced dose, resulting in reduce side effects.

In any of the above regimens, peppermint oil may be included in theformulation, either as immediate release, or, for example, may beenterically coated (e.g., alone with other components) for immediaterelease after several hours to target both the timing and location ofabdominal pain side effects associated with some therapeutic agents.

In should be noted that the above treatment regimens are not limiting onthe scope of the present invention. These treatment regiments can bealtered to include other pharmaceuticals, other formulations (e.g.,non-nanoparticulate, enteric coating, delayed release, immediaterelease, combinations thereof, etc.), other doses, additional doses,etc.

Example 3 Deterrent of Abuse

Stimulants, such as amphetamines and methylphenidate, are widely abusedas prescription products. The stimulants elevate the levels of dopamineas well as nor-epinephrine. Non-stimulants on the other hand act only byincreasing the levels of nor-epinephrine. Drugs that elevate dopamine(e.g. amphetamine, methamphetamine, cocaine) make people euphoric. Dueto this pharmacologic effect, stimulant drugs are abused whereasnon-stimulant drugs typically are not. According to the NationalInstitutes on Drug Abuse (part of the NIH) stimulants are abused forboth “performance enhancement” and recreational purposes. For theformer, they suppress appetite and facilitate weight loss. The euphoriceffects of stimulants usually occur when they are crushed and thensnorted or injected. Some abusers dissolve the tablets in water andinject the mixture.

In some embodiments, the present invention provides compositions,systems, and methods to deter the abuse of stimulant drugs in thetreatment of ADHD. In some embodiments, the present invention providescompositions and methods to deter subjects from taking unadvisable,off-prescription, and/or unintended dosages of pharmaceuticals of thepresent invention. In some embodiments, the present invention providescompositions and methods to deter subjects from taking and/oradministering pharmaceuticals of the present invention via unintended,off-prescription, and/or unadvisable routes (e.g. intravenously,snorting, etc.). In some embodiments, the present invention includes anabuse deterrent formulation for reducing the potential for one or moreof a) parenteral abuse, b) inhalation (e.g., intranasal abuse), and/orc) oral abuse of a drug, for satisfaction of a physical or psychologicaldependence. In some embodiments, the invention comprises combiningstimulant and non-stimulant drugs in a once daily dosing regimen, wherethe stimulant dose is reduced (e.g. reduced by 10-50%). In someembodiments, the invention provides stimulant and non-stimulant drugs ina tamper resistant formulation wherein the stimulant is combined with apolymer (e.g. polyethylene oxide, polyvinyl alcohol, hydroxypropylmethyl cellulose, carbomers, other such pharmaceutical agents, etc.) orsuitable pharmaceutical excipients to form a matrix that will make itdifficult for a person to abuse by dissolving the dosage form in wateror solvent and or snorting or injecting the solution. In someembodiments, the invention provides stimulant and non-stimulant drugscombined with an irritant. In some embodiments, reduction of stimulantdose, combination with an irritant, a formulation that is difficult totamper with, or a combination thereof provides a deterrent to abuse ofcompositions of the present invention.

In some embodiments, a pharmaceutical composition of the presentinvention comprises a surfactant present in sufficient amount to causenasal irritation. In some embodiments, a pharmaceutical composition ofthe present invention comprises an inert excipient in sufficient amountto cause emesis if greater than a prescribed amount included in thetherapeutic composition is ingested. In some embodiments, apharmaceutical composition of the present invention comprises an emeticin sufficient amount to cause emesis if greater than a prescribed amountof the analgesic included in the therapeutic composition is ingested. Insome embodiments, the amount of emetic present in a pharmaceuticalcomposition of the present invention can be tied directly to the amountof drug in the pharmaceutical composition. Thus, by controlling thequantity of the emetic compound in the pharmaceutical composition,emesis can be avoided if normal prescription directions are followed.However, if an overdosage occurs by ingesting more than a prescribedquantity of a drug in a pharmaceutical composition of the presentinvention, the amount of ingested emetic can exceed the threshold amountnecessary to induce emesis.

In some embodiments, the present invention deters inhalation abuse byproviding a pharmaceutical composition which includes one or more mucousmembrane, mucosa or mucosal tissue irritants (collectively referred toas mucous membrane irritants). In one embodiment, suitable mucousmembrane irritants and/or nasal passageway tissue irritants includecompounds that are generally considered pharmaceutically inert, yet caninduce irritation. Such compounds include, but are not limited tosurfactants. In some embodiments, suitable surfactants include sodiumlauryl sulfate, poloxamer, sorbitan monoesters, glyceryl monooleates,etc. Other suitable compounds are believed to be within the knowledge ofa practitioner skilled in the relevant art, and can be found in theHandbook of Pharmaceutical Excipients, 4th Ed. (2003), the entirecontent of which is hereby incorporated by reference. In someembodiments, two or more of the abuse deterrents can be combined intoone composition according to the present invention.

In some embodiments, the present invention incorporates or applies abusedeterrent compositions, dosages, and methods known in the art (U.S. Pat.No. 7,510,726; U.S. Pat. No. 7,476,402; herein incorporated by referencein their entireties). In some embodiments, the abuse deterrentcompositions and methods described herein find use with any embodimentsof the present invention.

Example 4 Nanoparticulate Formulation

In some embodiments, experiments were performed during development ofembodiments of the present invention to produce nanoparticles comprisingpharmaceutical compositions (e.g., mixture of amphetamines) with areduced particle size distribution. Experiments were conducted todecrease the particle size of an amphetamine mixture to a median sizebelow 400 nm. A milling procedure, in which active pharmaceuticalingredients (APIs), were milled together to produce nanoparticles, wasused. Successfully milled API was be loaded into hard gelatin capsulesfor use in a non-GLP in vivo study to compare pharmacokinetics to thecommercially available dosage form. The amphetamine milled was a 3:1 D:Lmixture of amphetamine isomers, obtained by preparing a 1:1 mixture ofamphetamine and the racemic mixture dextroamphetamine. The sulfate saltof each API was used for the project sourced from Johnson-Matthey Plc.

The inherent water solubility of the two amphetamine salts necessitatedmilling in non-aqueous vehicles. Vehicles were identified thatexhibited: 1) minimal solvency for the APIs, and 2) sufficientvolatility to allow for their removal to yield a dry powder of themilled material. Based on these criteria: ethyl acetate, methylenechloride, hexanes, and cyclomethicone were identified as potentialmilling vehicles.

The initial particle size distribution of the mixture was measured usinga Horiba LA-950V2 with a median size of approximately 32 nm (SEE FIG.1). Suspensions at 5% of the 1:1 mixture of amphetamine salts in each ofthe identified vehicles were made, and roller milled in 20 mL glassvials using 0.5 mm YTZ milling media. The vials were rolled on a USStoneware laboratory roller mill with particle size measured after fourand 16 hours of milling. No additives or dispersants were used in theseinitial trials so as not to complicate drying and recovery as tocalculation of yield.

Microscopic analysis revealed that the milling procedure resulted in asize reduction in all milling vehicles, though this was not indicated inthe PSD measurements using the Horiba due to agglomeration of the milledparticles. Additional measurements were made adding 0.1% oleic acid as adispersant to the cyclohexane used as diluent for the measurement,resulting smaller sizes, though still not representative to that seenmicroscopically (See Table 1).

TABLE 1 Roller Milling Results Median Particle Size [μ] Roller MillingPSD 0.1% Oleic PSD in acid in Cyclohexane Cyclohexane 24 hr w/ Solvent 4hr 16 hr 16 hr 24 hr 30 min sonic Ethyl Acetate 21.3 26.4  8.7 21.1 10.4(300 nm) Methylene 33.7 45.9 12.8 23.6  8.7 Chloride Hexane 13.5 Nosignal No signal  4.1 N/A Cyclomethicone 31.9 17.4  8.2 10.9 18.1 (300nm)Sonication was applied to the preparations which reduced size further,though not be representative of actual primary particle size observedmicroscopically.

Hexanes presented a particular issue in that the API particles appearedto fuse/heavily agglomerate to the media resulting in a lack ofmeasurable particles, and further work was discontinued using thisvehicle. Some samples did exhibit evidence of a bimodal distributionwith a population at the target range (values in parenthesis in Table1).

To speed the rate of milling, the ethyl acetate and methylene chloridesamples were transferred to spindle milling. In spindle milling, themedia is stirred rather than depending on gravity to move the media asin roller milling, allowing input of a higher level of energy to thegrinding. Some additional particle size reduction was found after twohours of spindle milling, though still not judged representative of thatobserved microscopically. In effort to disperse the observedagglomerates, a higher level of 0.5% oleic acid was tried for the PSDpreparation diluent, but did not provide appreciably better results (SeeTable 2). Graying of the samples was also observed likely due toabrasion of the stainless steel spindle, so this approach was notpursued further.

TABLE 2 Spindle Milling Results Median Particle Size [μ] Spindle MillingPSD 0.1% Oleic PSD 0.5% Oleic acid in Cyclohexane acid in Cyclohexane 2hr w/ 2 hr w/ Solvent 2 hr 5 min sonication 5 min sonication EthylAcetate 10.4 11.1  8.9 Methylene 17.6 11.6 10.5 Chloride

To determine if the cause of agglomeration was caused by overgrinding,an investigation was started to determine particle size versus millingtime. Roller milling in ethyl acetate with no milling aid or dispersantwas used, with particle size measured at initial and 30, 60, 120, and240 minutes. From these results, the progression of particle sizereduction was as desired and evidence of overgrinding was not observed(SEE FIGS. 2-11).

Experiments conducted during development of embodiments of the presentinvention indicated that APIs were milling well, but could not bedispersed well enough to accurately measure the primary particle size.Alternate dispersants were investigated to overcome this difficulty.Sedefos 75 (Gattefosse) was identified to provide good dispersion of themilled APIs for particle size measurement (SEE FIGS. 12 and 13).However, the Sedefos was also found to form micelles in ethyl acetate ofsimilar size, especially in the presence of trace water in the ethylacetate, leading to uncertainty of the accuracy of the measurement.During investigations, anhydrous ethanol was found to disperse the APIswell without the addition of any dispersant, and a milling trial wasperformed giving a median size of 200 nm after 40 hr of milling,measured without the addition of any dispersant (SEE FIGS. 14 and 15).The milling was performed at a loading of 5% of the amphetamine mixturein the ethanol.

Upon successfully milling the amphetamines, experiments were conductedto determine an appropriate drying procedure to maintain the milledparticle size. This was tested by redispersing in ethanol and measuringthe resultant particle size. First, ethanol was dried off under vacuum,though this resulted in irreversible particle size growth even withsonification to disperse the particles (SEE FIG. 16). It was nextattempted to lyophilize the milled dispersion. Lyophilization of thestraight suspension was also found to cause an increase in particlesize. However, the addition of 1% PVP K-29/32 to the milled suspensionas a cryoprotectant was found to adequately maintain particle size. Asecond larger batch was milled to be used to produce the test articlecapsules. This batch required 52 hr of milling to eliminate the tail oflarger sized particles. Upon completion of the milling, the suspensionwas harvested and modified with the addition of the PVP K-29/32. Thesuspension was lyophilized at −45° C./0.1 torr with a cycle time ofapproximately 17 hr. Post-lyophilized particle size was measured andfound to be similar to the pre-lyophilized size (SEE FIG. 17).

Twenty size 000 hard gelatin capsules were filled by hand on a 5-placeanalytical balance to a target fill of 11.3-11.5 mg. This target fillweight is the calculated equivalent of 6.3 mg of amphetamine in the freebase form (See Table 3)

TABLE 3 Calculation of Free-Base Equivalent Yield from Total Cake Weight555 mg Lyophilization PVP added pre lyophilization 135 mg AMP sulfatewt. in cake 420 mg Free base calculation AMP sulfate mw 368.49 AMP mw135.2 Salt is 2 AMP:1 H2SO4 270.4/368.49 % free-base in salt 73.38%Free-base target 6.3 mg free-base per capsule Salt equivalent  6.3mg/0.7338 8.59 mg salt Salt % less PVP  420 mg/555 mg 75.68% Fill wt.8.59 mg/0.7568 11.35 mg salt + PVP

Example 5 Bioanalysis of Nanoparticulates Administered to Subjects

A LC-MS/MS method was developed for the determination of bothl-amphetamine and d-amphetamine in mini-pig plasma (sodium heparin)using (d, 1)-amphetamine-d6 as an internal standard. Sample volume usedwas 100 μL of mini-pig plasma, with any necessary dilutions performed inblank mini-pig plasma prior to extraction. Sample clean-up consisted ofa liquid-liquid extraction of analyte into methyl tert-butyl ether(MTBE), followed by evaporation of the organic, and reconstitution inmobile phase. The d- and l-isomers of amphetamine were separated byliquid chromatography on a Chiral-CBH column from Chiral Technologies.An isocratic gradient using a mobile phase consisting of 6% acetonitrilein 10 mM ammonium acetate and 50 μM EDTA at 220 μL/min was used toseparate lamphetamine and d-amphetamine, with retention times ofapproximately 3.6 and 4.6 minutes, respectively, with a total run timeof 10 minutes. A calibration curve was prepared by spiking test compoundinto blank mini-pig plasma with a range from 0.5 ng/mL to 500 ng/mL.timepoints were taken at 15 minutes, 30 minutes, 45 minutes 1 hour, 1.5hours, 3 hours, 6 hours, 8 hours, and 24 hours. Date indicated thatplasma concentrations of d-amphetamine and l-amphetamine in pig plasmapeaked prior to the 15 minute timepoint and were being cleared over thefirst several time-points (e.g., 1.5 hours). For pharmacokinetic (PK)analysis, the drug had lower plasma concentrations for both the d- andl-forms of amphetamine. The corresponding PK parameters also reflectthis difference in lower AUC. PK analysis demonstrated that both the d-and l-forms of amphetamine were rapidly cleared, and indicated that thepeak concentration in plasma occurred prior to the 15 minute time-point.Such rapid clearance was unexpected.

Example 6 Dose-Normalized PK Analysis

Capsule analysis was performed on the dosing capsules used for the PKanalysis described in Example 5. Capsule analysis revealed that thedosing capsule contained an average of 0.705 mg of total amphetamine feebase. This corresponds to 0.962 mg of total amphetamine sulfate.Collection of time points at earlier intervals (e.g., 1 min., 5 min.,etc.) may reveal earlier and higher PK and resultant higherbioavailability. For an accurate comparison with the Adderall, the PKparameters for C_(max) and AUC were dose-normalized (See Tables 4-7).

TABLE 4 Normalized PK Analysis of d-Amphetamine from 10 mg InnovatorDose 10 mg oral innovator dose, Leg 1, 1-amphetamine Pig ID # Time (hr)1.51 1.52 1.53 1.54 1.55 1.56 AVG SD 0 BLQ BLQ BLQ BLQ BLQ BLQ ND ND0.25 BLQ 1.95 4.97 BLQ 0.64 3.93 4.22 1.62 0.5 BLQ 2.00 3.60 1.60 4.293.08 2.93 1.10 1 0.611 2.00 2.85 2.30 3.30 2.97 2.32 0.968 1.5 BLQ 1.772.35 1.77 2.23 2.80 2.19 0.435 3 BLQ 0.983 1.01 0.202 2.23 2.00 1.510.755 6 BLQ BLQ 0.595 BLQ 0.779 BLQ 0.687 ND 8 BLQ BLQ BLQ BLQ BLQ BLQND ND 24 BLQ BLQ BLQ BLQ BLQ BLQ ND ND Animal 18.8 19.3 16.5 19.7 20.019.5 19.0 1.27 Weight (kg) Amount 0.962 0.962 0.962 0.962 0.962 0.962n/a n/a dosed (mg) C

0.611 2.09 4.97 2.10 1.04 3.93 0.22 1.94 t

1 1 0.29 1 0.25 0.25 0.625 0.411 T

n/a 1.05 2.23 1.41 2.62 3.40 2.14 0.941 AUC

0.153 4.51 11.6 4.92 13.1 7.92 6.88 4.92 AUC

n/a 5.39 13.5 5.65 16.0 17.7 11.6 5.79 Dose normalized C

0.635 2.03 5.37 2.30 5.86 4.09 3.35 2.01 AUC

0.159 4.69 12.1 4.30 13.6 8.23 7.16 0.12 AUC

n/a 5.00 14.0 5.07 16.6 18.4 12.1 6.02 *

indicates data missing or illegible when filed

TABLE 5 Normalized PK Analysis of 1-Amphetamine from 10 mg InnovatorDose 10 mg oral innovator dose, Leg 1, 1-amphetamine Pig ID # Time (hr)1.51 1.52 1.53 1.54 1.55 1.56 AVG SD 0 BLQ BLQ BLQ BLQ BLQ BLQ ND ND0.25 BLQ 0.792 1.64 BLQ 1.64 1.30 1.34 0.401 0.5 BLQ BLQ 1.16 0.535 1.260.787 0.023 0.344 1 BLQ 0.727 0.788 0.585 0.961 0.995 0.811

1.5 BLQ 0.52 0.753 BLQ 0.704 0.296 0.653 0.121 3 BLQ BLQ 0.523 BLQ 0.672BLQ ND ND 6 BLQ BLQ BLQ BLQ BLQ BLQ ND ND 8 BLQ BLQ BLQ BLQ BLQ BLQ NDND 24 BLQ BLQ BLQ BLQ BLQ BLQ ND ND Animal 18.2 10.3 16.5 19.7 20.0 19.510.0 1.37 Weight (kg) Amount 0.962 0.962 0.962 0.962 0.962 0.962 n/a n/adosed (mg) C

n/a 0.792 1.64 0.585 1.64 1.36 1.39 0.489 t

n/a 0.25 0.25 1 0.25 0.25 0.420 0.335 T

n/a n/a 3.24 n/a n/a n/a n/a n/a AUC

n/a 0.692 2.38 0.339 2.57 1.32 1.45 0.993 AUC

n/a n/a 4.83 n/a n/a n/a n/a n/a Dose normalized C

n/a 0.823 1.70 0.608 1.70 1.35 1.24 0.504 AUC

n/a 0.719 2.47 0.352 2.67 1.37 1.52 1.03 AUC

n/a n/a 5.02 n/a n/a n/a 3.02 n/a

indicates data missing or illegible when filed

TABLE 6 Normalized PK Analysis of d-Amphetamine from 10 mg Adderall 10mg oral Adderall dose, Leg 2, d amphetamine Pig ID # Time (hr) 1.51 1.521.53 1.54 1.55 1.56 AVG SD 0 BLQ BLQ BLQ BLQ BLQ BLQ ND ND 0.25 6.8023.7 3.66 2.99 BLQ 9.97 9.42 8.45 0.5 7.54 58.1 9.10 4.15 7.99 38.1 20.822.1 1 13.2 23.2 21.7 15.4 15.3 18.7 17.8 3.06 1.5 11.0 21.8 21.4 13.511.7 18.0 15.2 4.82 3 8.45 15.4 18.3 9.11 9.07 12.6 12.2 4.03 6 2.354.07 8.26 2.36 1.58 4.33 3.79 2.42 8 0.853 1.73 3.08 1.37 0.931 1.601.58 0.808 24 BLQ BLQ BLQ BLQ BLQ BLQ ND ND Animal 19.3 19.5 21.8 21.220.3 20.2 20.4 0.966 Weight (kg) Amount 10 10 10 10 10 10 n/a n/a dosed(mg) C

13.2 52.1 21.7 15.4 15.3

27.9 17.9 t

1 0.5 1 1 1 0.5 0.833 0.258 T

1.52 3.58 1.99 1.88 1.64 1.69 1.72 0.182 AUC

47.9 1.08 101 51.3 47.6 84.4 73.4 27.9 AUC

49.7 112 110 55.0 49.8 88.3 77.5 29.7 Dose normalized C

1.32 5.81 2.17 1.54 3.53 3.81 2.78 1.78 AUC

4.79 10.8 10.1 5.13 4.76 8.44 7.34 2.79 AUC

4.97 11.2 11.0 5.50 4.98 8.83 7.75 2.97

indicates data missing or illegible when filed

TABLE 7 Normalized PK Analysis of 1-Amphetamine from 10 mg Adderall PigD # Time (km) 1.51 1.52 1.53 1.54 1.55 1.56 AVG SD 0 BLQ BLQ BLQ BLQ BLQBLQ ND ND 0.25 1.94 6.33 1.06 0.83 BLQ 2.5 2.55 2.23 0.5 2.13 15.2 2.491.06 2.18 11.0 5.68 5.92 1 3.30 6.24 4.78 3.56 3.29 4.98 4.36 0.18 1.52.62 5.14 4.89 3.28 0.25 4.77 3.83 0.26 3 1.96 3.53 4.05 2.21 1.52 1.992.76 0.910 6 BLQ 0.831 1.46 0.617 BLQ 1.05 0.903 0.360 8 BLQ BLQ 0.585BLQ BLQ BLQ ND ND 24 BLQ BLQ BLQ BLQ BLQ BLQ ND ND Animal 19.3 19.5 21.821.2 20.3 20.2 20.4 0.966 Weight (kg) Amount 10 10 10 10 10 30 n/a n/adosed (mg) C

3.30 15.2 4.80 3.56 3.29 11.5 6.87 5.04 t

1 0.5 1.5 1 1 0.5 0.917 0.376 T

2.83 1.67 1.53 1.83 n/a 2.05 2.04 0.463 AUC

7.02 24.7 21.8 11.6 6.08 20.3 153 8.04 AUC

15.0 26.7 23.4 13.2 n/a 23.4 20.3 5.89 Dose normalized C

0.330 1.52 0.489 0.356 0.329 1.50 0.687 0.304 AUC

0.702 2.47 2.18 1.16 0.608 1.03 1.53 0.804 AUC

1.50 2.57 2.34 1.32 n/a 1.34 2.03 0.589

indicates data missing or illegible when filed

D can also be represented by normalizing the nanoparticle formulation(innovator data) rather than revising the Adderall data (See Tables8-9).

TABLE 8 Un-normalized PK data d amphetamine l amphetamine time innAdderall time inn Adderall 0 MD MD 0 MD MD 0.25 4.12 5.42 0.25 1.34 2.850.5 2.85 20.5 0.5 0.831 5.86 1 2.32 17.9

0.011 4.30 1.5 2.10 18.2 1.5 0.603 3.83 3 1.51 12.2 3

2.76 6 0.087 3.78 6 MD 0.180 8 MD 1.50 8 MD MD 24 MD MD 24 MD MD

indicates data missing or illegible when filed

TABLE 9 Normalized PK data (scaling of nanoparticle formulation data)d-amphetamine l-amphetamine time

Adderall time

Adderall 0 MD MD 0 MD MD 0.25 42.8 9.42 0.25 14.6 2.85 0.5 30.4 20.8 0.30.67 5.86 1 24.1 17.9 1 0.43 4.36 1.5 22.7 18.2 1.3 7.21 3.83 3 10.612.2 3 6.21 2.76 6 7.14 3.79 5 MD 0.100 8 MD 1.00 6 MD MD 24 MD MD 24 MDMD

indicates data missing or illegible when filed

The capsule analysis data indicate that the actual dose used in theexperiments described in Example 5 was 1/10 of the labeled dose ofamphetamine. The revised data indicate that the nanoparticulateamphetamine has a higher cmax (3.35 ng/ml vs 2.70 ng/ml for Adderall),as well as a very fast onset of absorption (Table 4 and 6). These dataindicate that there is no degradation of amphetamine in thenanoparticulate formulation, and lower content detected in initial dataanalysis was due to content non-uniformity of powder. These data alsoindicate that the bioavailability of nanoparticle formulation ofamphetamine sulphate is higher than currently FDA-approved formulationof Adderall, and that improved bioavailable nanoparticle formulation canbe used in combination with non-stimulants. The data indicate theusefulness of nanoparticulate formulations for: immediate releasestimulant (e.g., amphetamine), lower dose and comparable efficacy tonon-nanoparticulate formulation, orally disintegrating tabletformulation providing rapid drug release through the oral mucosa, fastonset dose (e.g., when fast onset is desired, in addition to currenttherapy where control of ADHD may not be sufficient, etc.),coadministration with a suitable slow release component (e.g., toprovide immediate and prolonged treatment), rapid-release formulations(e.g., 15-30 minutes), etc.

Example 7 Safety and Efficacy of a Once Daily Fixed Dose SequentialRelease Formulation of Stimulant Followed by Non-Stimulant

Experiments are contemplated to evaluate the safety and effectiveness ofa once-daily fixed-dose sequential-release formulation of stimulant(amphetamine) and non-stimulant (guanfacine) compared to placebo inchildren ages 6-14. Experiments test suitability of the once-dailyfixedose sequential-release formulation of stimulant followed bynon-stimulant to address the challenges with current therapies. Theeffectiveness & safety of a test formulation in which the daily dose ofthe stimulant is significantly reduced and released early in the dayonly, followed by lower dose of non-stimulant released to providecoverage for the latter half of the day will be assessed. Due to thefast elimination of stimulants, the drug levels of stimulant in the testformulation towards the end of the day will be extremely low compared toall once daily drugs currently on the market.

Experiments are performed in a randomized, multi-center,placebo-controlled, parallel-group, forced dose titration in whichchildren (ages 6-12 years) with ADHD will be randomized to once-dailyfixed-dose sequential-release formulation (amphetamine immediate releasenanoparticles+guanfacine delayed release: 5+1 mg, 10+2 mg or 15+3 mg) orplacebo for four weeks of double-blind evaluation of safety andefficacy. Subjects will be screened to establish eligibility for studyparticipation. Subjects meeting eligibility requirements will undergomedication washout, if applicable, for 7-28 days. Following washout,subjects will return to the clinic for reassessment of eligibilitycriteria and establishment of baseline measures. Eligible subjects withbaseline ADHD-RS score greater than or equal to 28 will be randomized totreatment. Eligible subjects will be randomly assigned (in a 2:2:2:1ratio of each of the three doses vs. placebo) to a daily morning dose ofonce-daily fixed-dose sequential-release formulation or placebo for 4weeks. Once-daily fixed-dose sequential-release formulation groups willstart with a dose of 5+1 mg/day. Subjects randomized to 15+3 mg will betitrated to that dose over a 2 week period; those randomized to 10+2 mgwill be titrated that dose over a 1 week period; and those randomized to5+1 mg will begin dosing on the 5+1 mg per day during week 1 and willremain on that dose throughout the study. Double-blind assessment of thesafety and efficacy of the New Formulation will proceed for 4 weeks withweekly clinic visits schedule for evaluations and medicationdisbursements. Subjects who have completed at least 2 weeks ofdouble-blind participation will have the option to continueparticipation in an open label extension study. Subjects who are noteligible or who choose not to participate in the extension study willcontinue to be followed for 30 days following their last dose of studydrug.

In some embodiments, Health Related Quality of Life (HRQL) improvementswill be measured for the trial using Child Health & Ilness Profile(CHIP) to assess HRQL Total Global Score of the CHIP will be an outcomemeasure.

Additional studies are contemplated according to the above protocol oraltered protocols using different combinations of stimulant (e.g.,amphetamine (e.g., Adderall, Adderal XR, Adderal IR, etc.),methylphenidate (e.g., Ritalin, Methylin, Ritalin SR, Metadate ER,Methylin, Methylin ER, Concerta, Metadate CD, Ritalin LA, etc.),dexmethylphanidate (e.g., Focalin), lisdexamfetamine (e.g., Vyvanse),etc.) and non-stimulant (e.g., Atomoxetine, Guanfacine, and Clonidine),different dosages, different time-release profiles (e.g., slow release,immediate release, delayed release, single peak release, multi-peakrelease, etc.), different formulations (e.g., nanoparticulateformulation, non-nanoparticulate, etc.), etc.

Although the invention has been described in connection with specificpreferred embodiments, it should be understood that the invention asclaimed should not be unduly limited to such specific embodiments.Indeed, various modifications of the described modes for carrying outthe invention that are obvious to those skilled in the relevant fieldsare intended to be within the scope of the following claims.

1. A once-daily pharmaceutical composition comprising: a) anorepinephrine reuptake inhibitor stimulant; and b) an alpha adrenergicagonist non stimulant; wherein the pharmaceutical composition isformulated for sequential release of the norepinephrine reuptakeinhibitor stimulant and the alpha adrenergic agonist non stimulant, andwherein said once-daily pharmaceutical composition provides a reductionin side effects compared to a therapeutic once-daily dose of saidnorepinephrine reuptake inhibitor stimulant alone.
 2. The once-dailypharmaceutical composition of claim 1, wherein said reduction in sideeffects comprises reduction in one or more of appetite suppression,insomnia, gastrointestinal pain, and stunted growth.
 3. A pharmaceuticalcomposition comprising: a) an amount of norepinephrine reuptakeinhibitor stimulant that is subtherapeutic for once dailyadministration; and b) an alpha adrenergic agonist non stimulant;wherein the pharmaceutical composition is formulated for sequentialrelease of the norepinephrine reuptake inhibitor stimulant and the alphaadrenergic agonist non stimulant, and wherein sequential release of thenorepinephrine reuptake inhibitor stimulant and the alpha adrenergicagonist non stimulant provides therapeutic effectiveness for once dailyadministration.
 4. A pharmaceutical composition of claim 3, wherein saidalpha adrenergic agonist non stimulant is present in an amount that issubtherapeutic for once daily administration.
 5. A pharmaceuticalcomposition comprising: a) a norepinephrine reuptake inhibitorstimulant; and b) an alpha adrenergic agonist non stimulant; wherein thepharmaceutical composition is formulated for sequential release of thenorepinephrine reuptake inhibitor stimulant between 0 and 2 hours andthe alpha adrenergic agonist non stimulant between 2 and 9 hours, andwherein sequential release of the norepinephrine reuptake inhibitorstimulant and the alpha adrenergic agonist non stimulant providestherapeutic effectiveness for once daily administration.
 6. Thepharmaceutical composition of claim 5, wherein said sequential releaseprovides a reduction in side effects compared to a therapeuticonce-daily dose of said norepinephrine reuptake inhibitor stimulantalone.
 7. The pharmaceutical composition of claim 1, wherein thenorepinephrine reuptake inhibitor stimulant is formulated to beginrelease upon administration to a subject.
 8. The pharmaceuticalcomposition of claim 1, wherein the norepinephrine reuptake inhibitorstimulant is formulated for release between 0 and 2 hourspost-administration.
 9. The pharmaceutical composition of claim 1,wherein the norepinephrine reuptake inhibitor stimulant isnanoparticulate formulated.
 10. The pharmaceutical composition of claim1, wherein the alpha adrenergic agonist non stimulant is coated forenteric release.
 11. The pharmaceutical composition of claim 1, whereinthe alpha adrenergic agonist non stimulant is formulated for releasebetween 2 and 9 hours post-administration.
 12. The pharmaceuticalcomposition of claim 3, wherein the amount of norepinephrine reuptakeinhibitor stimulant is at least 20% less than a therapeutic formulation.13. The pharmaceutical composition of claim 12, wherein the amount ofnorepinephrine reuptake inhibitor stimulant is 5-15 mg.
 14. Thepharmaceutical composition of claim 13, wherein the amount ofnorepinephrine reuptake inhibitor stimulant is about 10 mg.
 15. Thepharmaceutical composition of claim 3, wherein the amount of alphaadrenergic agonist non stimulant is at least 20% less than a therapeuticformulation.
 16. The pharmaceutical composition of claim 15, wherein theamount of alpha adrenergic agonist non stimulant is 1-4 mg.
 17. Thepharmaceutical composition of claim 16, wherein the amount of alphaadrenergic agonist non stimulant is about 2 mg.
 18. The pharmaceuticalcomposition of claim 1, wherein the norepinephrine reuptake inhibitorstimulant is selected from amphetamines, lisdexamphetamines,methylphenidates, dexmethylphenidates, and dexamphetamines.
 19. Thepharmaceutical composition of claim 1, wherein the alpha adrenergicagonist non stimulant is selected from atomoxetine, guanfacine, andclonidine.
 20. A method of treating ADHD by administering apharmaceutical composition of claim 1, to a subject, wherein thepharmaceutical composition is administered once per day to the subject,and wherein said subject is a child, adolescent, or adult.
 21. A methodof treating ADHD symptoms while reducing adverse stimulant-related sideeffects by administering a once-daily pharmaceutical compositioncontaining an otherwise subtherapeutic dose of a stimulantpharmaceutical agent, the pharmaceutical composition comprising: (a) ananoparticulate formulated stimulant; (b) stimulant formulated for earlyor immediate release; (c) both stimulant pharmaceutical agent andnon-stimulant pharmaceutical agent; or (d) a combination of two or moreof (a), (b), and (c).
 22. The method of claim 21, wherein the adversestimulant-related side effects comprise appetite suppression.
 23. Themethod of claim 22, wherein the appetite suppression manifests as weightloss in a subject.
 24. The method of claim 21, wherein the adversestimulant-related side effects comprise insomnia.
 25. The method ofclaim 21, wherein the adverse stimulant-related side effects comprisestunted growth of a subject.
 26. A pharmaceutical composition fortreating ADHD symptoms with a once-daily stimulant pharmaceutical agentwhile reducing gastrointestinal adverse side effects comprisingadministering a pharmaceutical composition comprising: (a) an immediate-or early-release pharmaceutical formulation comprising an amount ofstimulant pharmaceutical agent that is subtherapeutic for once dailyadministration; and (b) a delayed-release pharmaceutical formulationcomprising: (i) a non-stimulant pharmaceutical agent, an amount ofstimulant pharmaceutical agent that is subtherapeutic for once dailyadministration, and peppermint oil; (ii) a non-stimulant pharmaceuticalagent and peppermint oil; or (iii) a non-stimulant pharmaceutical agent.27. The pharmaceutical composition of claim 26, wherein the immediate-or early-release pharmaceutical formulation provides release between 0and 2 hours post-administration.
 28. The pharmaceutical composition ofclaim 27, wherein the immediate- or early-release pharmaceuticalformulation comprises nanoparticulate formulation.
 29. Thepharmaceutical composition of claim 26, wherein the stimulantpharmaceutical agent formulated for immediate- or early-release isselected from amphetamines, lisdexamphetamines, methylphenidates,dexmethylphenidates, and dexamphetamines.
 30. The pharmaceuticalcomposition of claim 26, wherein the amount of stimulant pharmaceuticalagent in the immediate- or early-release pharmaceutical formulation isabout 5-15 mg.
 31. The pharmaceutical composition of claim 26, whereinthe delayed-release pharmaceutical formulation provides release between2 and 9 hours post-administration.
 32. The pharmaceutical composition ofclaim 31, wherein the delayed-release is provided by an enteric coatingcoated.
 33. The pharmaceutical composition of claim 26, wherein thenon-stimulant pharmaceutical agent selected from Atomoxetine,Guanfacine, and Clonidine.
 34. The pharmaceutical composition of claim33, wherein the delayed-release pharmaceutical formulation comprisesabout 1-3 mg of non-stimulant.
 35. The pharmaceutical composition ofclaim 26, wherein the delayed-release pharmaceutical formulationcomprises amount of stimulant pharmaceutical agent that issubtherapeutic for once daily administration, wherein the amount isabout 3-8 mg.
 36. The pharmaceutical composition of claim 35, whereinthe stimulant pharmaceutical agent is selected from amphetamines,lisdexamphetamines, methylphenidates, dexmethylphenidates, anddexamphetamines.
 37. A method of treating ADHD in an adult, child, oradolescent subject by administering a pharmaceutical composition ofclaim 26 to the subject, wherein the pharmaceutical composition isadministered once per day to the subject.
 38. A rapid onset stimulantpharmaceutical formulation comprising nanoparticulate formulatedstimulant and a pharmaceutically acceptable carrier.
 39. Thepharmaceutical formulation of claim 38, comprising an amount ofstimulant pharmaceutical agent that is subtherapeutic for once dailyadministration.
 40. The pharmaceutical composition of claim 39, whereinthe amount of stimulant pharmaceutical agent is at least 20% less than atherapeutic formulation.
 41. The pharmaceutical composition of claim 38,wherein the stimulant pharmaceutical agent is formulated for releasebetween 0 and 2 hours post-administration.
 42. The pharmaceuticalcomposition of claim 38, wherein the particles in the nanoparticulateformulation are less than 1000 microns in diameter.
 43. Thepharmaceutical composition of claim 42, wherein the nanoparticulateformulation has a mean nanoparticle diameter of 100-500 nm.
 44. A methodof treating ADHD by administering a rapid onset stimulant pharmaceuticalcomposition of claim 38 to a subject.
 45. A pharmaceutical compositionfor extended duration of treatment of ADHD symptoms comprising: (a) animmediate- or early-release pharmaceutical formulation comprising anamount of stimulant pharmaceutical agent that is subtherapeutic for oncedaily administration; and (b) a delayed-release pharmaceuticalformulation comprising a non-stimulant pharmaceutical agent.
 46. Thepharmaceutical composition of claim 45, wherein the immediate- orearly-release pharmaceutical formulation provides release between 0 and2 hours post-administration.
 47. The pharmaceutical composition of claim46, wherein the immediate- or early-release pharmaceutical formulationcomprises nanoparticulate formulation.
 48. The pharmaceuticalcomposition of claim 45, wherein the stimulant pharmaceutical agentformulated for immediate- or early-release is selected fromamphetamines, lisdexamphetamines, methylphenidates, dexmethylphenidates,and dexamphetamines.
 49. The pharmaceutical composition of claim 48,wherein the amount of stimulant pharmaceutical agent in the immediate-or early-release pharmaceutical formulation is about 5-15 mg.
 50. Thepharmaceutical composition of claim 45, wherein the delayed-releasepharmaceutical formulation provides release between 2 and 9 hourspost-administration.
 51. The pharmaceutical composition of claim 50,wherein the delayed-release is provided by an enteric coating coated.52. The pharmaceutical composition of claim 45, wherein thenon-stimulant pharmaceutical agent selected from Atomoxetine,Guanfacine, and Clonidine.
 53. The pharmaceutical composition of claim52, wherein the delayed-release pharmaceutical formulation comprisesabout 1-4 mg of non-stimulant.
 54. The pharmaceutical formulation ofclaim 45, wherein the delayed-release pharmaceutical formulation furthercomprises a second amount of stimulant pharmaceutical agent that issubtherapeutic for once daily administration.
 55. The pharmaceuticalcomposition of claim 54, wherein the second amount of stimulantpharmaceutical agent is about 3-8 mg.
 56. The pharmaceutical compositionof claim 55, wherein the stimulant pharmaceutical agent is selected fromamphetamines, lisdexamphetamines, methylphenidates, dexmethylphenidates,and dexamphetamines.
 57. A method of treating ADHD by administering apharmaceutical composition of claim 45 to a subject, wherein thepharmaceutical composition is administered once per day to the subject.58. A method for producing an amphetamine nanoparticulate formulationcomprising: (a) forming a mixture of amphetamine and one or morevehicles; (b) milling the mixture; and (c) drying the mixture.
 59. Themethod of claim 58, wherein the amphetamine comprises l-amphetamine,d-amphetamine.
 60. The method of claim 58, wherein the particles in theamphetamine nanoparticulate formulation are less than 1000 microns indiameter.
 61. The method of claim 58, wherein the amphetaminenanoparticulate formulation has a mean nanoparticle diameter of 100-500nm.
 62. A pharmaceutical composition comprising a stimulantpharmaceutical agent and a non-stimulant pharmaceutical agent, whereinthe upon administration to a subject, the pharmaceutical compositionprovides a plasma concentration profile comprising a stimulant maximumbetween 0 and 2 hours post-administration and a non-stimulant maximumbetween 2 and 9 hours post-administration.
 63. The pharmaceuticalcomposition of claim 62, all or a portion of the stimulantpharmaceutical agent is nanoparticulate formulated.
 64. Thepharmaceutical composition of claim 62, wherein the stimulantpharmaceutical agent is selected from amphetamines, lisdexamphetamines,methylphenidates, dexmethylphenidates, and dexamphetamines.
 65. Thepharmaceutical composition of claim 62, wherein the stimulant maximumbetween 0 and 2 hours post-administration is the effect of about 5-15 mgof the stimulant pharmaceutical agent.
 66. The pharmaceuticalcomposition of claim 62, wherein the non-stimulant pharmaceutical agentis enterically coated.
 67. The pharmaceutical composition of claim 62,wherein the non-stimulant pharmaceutical agent is selected fromAtomoxetine, Guanfacine, and Clonidine.
 68. The pharmaceuticalcomposition of claim 62, wherein the plasma concentration profilecomprises a second stimulant maximum between 2 and 7 hourspost-administration.
 69. The pharmaceutical composition of claim 68,wherein the stimulant pharmaceutical agent that gives rise to the secondstimulant maximum is selected from amphetamines, lisdexamphetamines,methylphenidates, dexmethylphenidates, and dexamphetamines.
 70. Thepharmaceutical composition of claim 68, wherein the second stimulantmaximum between 2 and 7 hours post-administration is the effect of about3-8 mg of stimulant pharmaceutical agent.
 71. The pharmaceuticalcomposition of claim 68, wherein the stimulant pharmaceutical agent thatgives rise to the second stimulant maximum is enterically coated.
 72. Amethod of treating ADHD symptoms in a subject comprising administering apharmaceutical composition of claim 62 to the subject.
 73. Apharmaceutical composition for treatment of the symptoms of ADHDcomprising: (a) a once-daily therapeutic dose of a stimulantpharmaceutical agent; and (b) a dose of a non-stimulant pharmaceuticalagent; wherein the stimulant pharmaceutical agent and the non-stimulantpharmaceutical agent are formulated for sequential release, and whereinco-administration of said stimulant pharmaceutical agent and saidnon-stimulant pharmaceutical agent provides enhanced efficacy overadministration of a once-daily stimulant pharmaceutical agent alone. 74.The pharmaceutical composition of claim 73, wherein said stimulantpharmaceutical agent is nanoparticulate formulated.
 75. Thepharmaceutical composition of claim 73, wherein the non-stimulantpharmaceutical agent is selected from Atomoxetine, Guanfacine, andClonidine.
 76. The pharmaceutical composition of claim 73, wherein thestimulant pharmaceutical agent is selected from amphetamines,lisdexamphetamines, methylphenidates, dexmethylphenidates, anddexamphetamines.
 77. The pharmaceutical composition of claim 73, whereinstimulant pharmaceutical agent is released between 0 and 2 hourspost-administration.
 78. The pharmaceutical composition of claim 73,wherein the non-stimulant pharmaceutical agent is released between 2 and7 hours post-administration.
 79. The pharmaceutical composition of claim77, wherein said stimulant is nanoparticulate formulated.
 80. Thepharmaceutical composition of claim 78, wherein said non-stimulant isformulated with an enteric coating.
 81. A method of treating a subjectfor ADHD symptoms comprising administering dose of stimulant in themorning and a dose of non-stimulant in the afternoon to reduce sideeffects and improve quality of life over stimulant-only therapies. 82.The method of claim 81, wherein said stimulant and non-stimulant areadministered in a single pharmaceutical composition, wherein saidstimulant is configured for immediate release and said non-stimulant isconfigured for delayed-release.
 83. The pharmaceutical composition ofclaim 81, wherein the non-stimulant pharmaceutical agent is selectedfrom Atomoxetine, Guanfacine, and Clonidine.
 84. The pharmaceuticalcomposition of claim 81, wherein the stimulant pharmaceutical agent isselected from amphetamines, lisdexamphetamines, methylphenidates,dexmethylphenidates, and dexamphetamines.
 85. The pharmaceuticalcomposition of claim 81, wherein stimulant pharmaceutical agent isreleased between 0 and 2 hours post-administration.
 86. Thepharmaceutical composition of claim 81, wherein the non-stimulantpharmaceutical agent is released between 2 and 7 hourspost-administration.
 87. The pharmaceutical composition of claim 81,wherein said stimulant is nanoparticulate formulated.
 88. Thepharmaceutical composition of claim 81, wherein said non-stimulant isformulated with an enteric coating.